Sébastien Leterme

Morgane Michaud
email: morgane.michaud@cea.fr

Non-vesicular glycerolipids transport in plant cells

Keywords: Non-vesicular lipid transport, Membrane contact sites, Membrane biogenesis, Lipid transfer proteins, Glycerolipids, Plants vesicular lipid transport in plant cells

In Eukaryotic cells, organelles are delineated by one or several membranes that are composed of a specific assembly of lipids and proteins ensuring the identity of each cell compartment and regulating their biogenesis and function. Lipids regulate many aspects of cell biology including vesicular trafficking, protein targeting, programmed cell death or signaling. They also play key roles in response to stress, which is particularly important for organisms such as plants that constantly cope with a multitude of environmental variations. Membranes are mainly composed of glycerolipids, sterols and sphingolipids. Lipid precursors are primarily synthesized in plastids and in the endoplasmic reticulum. Then, they have to be specifically directed to other cell compartments where they can be modified and transported to other organelles to regulate membrane biogenesis and function. Thus, lipid transfer is a key process involved in the maintenance of membrane homeostasis, in particular in stress conditions. Lipid exchanges between organelles can rely on vesicular or nonvesicular transport. Whereas vesicular transport concerns mainly organelles connected to the endomembrane system, such as the Golgi, vacuoles or the plasma membrane, non-vesicular lipid trafficking concerns virtually all organelles. This lipid transfer mechanism is thought to occur at membrane contact sites, corresponding to specific cell structures formed by the close apposition of two membranes at a distance ≤30nm. In this chapter, we will summarize our current knowledge about the mechanisms involved in non-vesicular lipid transport in plant cells, with a particular focus on glycerolipids, the main components of organelle membranes.

Introduction 1.Glycerolipid synthesis in plant cells

Glycerolipids are composed of a glycerol backbone esterified with two fatty acids (FAs) in position sn-1 and sn-2 (Figure 1A). FAs are defined by the length of their carbon chain and the number of double bonds (or unsaturations). In Arabidopsis thaliana, glycerolipid acyl-chains are mainly composed of 16 or 18 carbons (C16, C18) with up to three unsaturations (C16:0 to C16:3 and C18:0 to C18:3) [START_REF] Li-Beisson | Acyl-Lipid Metabolism[END_REF]. The nature of the polar head associated to the position sn-3 will define the class of the glycerolipid molecule. Three main classes are found in plants: 1) the phospholipids, containing a phosphate (Pi) moiety, 2) the galactoglycerolipids, containing one or two galactose residues for the monogalactosyldiacylglycerol (MGDG) or the digalactosyldiacylglycerol (DGDG) respectively, and 3) the sulpholipid sulphoquinovosyldiacylglycerol (SQDG), containing a sulphoquinovosyl group in its polar head (Figure 1B). Galactoglycerolipids and SQDG are the main constituents of plastid membranes, where they play a major structural and functional role in photosynthesis, whereas phospholipids are the main glycerolipids found in extra-plastidial membranes. Enzymes involved in the synthesis of galactoglycerolipids, SQDG and of plastidial phosphatidylglycerol (PG) are localized in plastid envelopes [START_REF] Boudière | Glycerolipids in photosynthesis : Composition, synthesis and trafficking[END_REF][START_REF] Li-Beisson | Acyl-Lipid Metabolism[END_REF]. Enzymes involved in phospholipids synthesis are mainly located in the endoplasmic reticulum (ER) and some are also found in mitochondria or in the endomembrane system [START_REF] Li-Beisson | Acyl-Lipid Metabolism[END_REF][START_REF] Michaud | Glycerolipid synthesis and lipid trafficking in plant mitochondria[END_REF]. In plants, FA biosynthesis occurs in the plastid stroma and gives rise to C16:0-acyl carrier protein (ACP) and C18:1-ACP (Li et al., 2016). These acyl-chains can then be directly used to feed the synthesis of plastidial lipids by the so-called Prokaryotic pathway or they can be exported in the cytosol and integrated into glycerolipids in the ER by the so-called Eukaryotic pathway [START_REF] Labrant | Lipid transport required to make lipids of photosynthetic membranes[END_REF][START_REF] Li-Beisson | Acyl-Lipid Metabolism[END_REF]. These two pathways lead to the biogenesis of phosphatidic acid (PA) and diacylglycerol (DAG), two precursor molecules that will be used to synthesize the whole set of plant glycerolipids (Figure 1). Importantly, after their synthesis, glycerolipid molecules can be subjected to a wide variety of modifications, such as acyl-chain remodeling or polar head modifications, combined to their transport to different cell compartments or translocation from one membrane leaflet to another. The vast variety of pathways involved in these processes highlights the complexity of maintaining membrane lipid homeostasis.

1.2 Non-vesicular glycerolipid transport in plant cells 1.2.1 Where does non-vesicular glycerolipid transport occur in plant cells?

Lipid transport can be mediated by vesicular or non-vesicular pathways. The vesicular pathway involves the transport of lipids, as well as proteins and soluble molecules, in vesicles that will emerge from a donor organelle, be transported through the cytosol and finally fuse with the acceptor organelle to deliver their content. This trafficking route concerns organelles connected to the endomembrane system, such as the ER, the vacuole, the Golgi or the plasma membrane (PM) [START_REF] Cevher-Keskin | Endomembrane Trafficking in Plants[END_REF]. In plants, vesicular transport also occurs in plastid stroma where this process is involved in the synthesis of thylakoids [START_REF] Lindquist | Chloroplast vesicle transport[END_REF]. Non-vesicular lipid transport corresponds to the direct transfer of lipid molecules from one membrane to another. This process is involved in the biogenesis of virtually all organelles, but those not connected to the vesicular transport pathway, like mitochondria or plastids, are completely dependent on this lipid transport route to ensure their biogenesis and function [START_REF] Bayer | From shaping organelles to signalling platforms : The emerging functions of plant ER-PM contact sites[END_REF][START_REF] Hurlock | Lipid Trafficking in Plant Cells[END_REF][START_REF] Labrant | Lipid transport required to make lipids of photosynthetic membranes[END_REF][START_REF] Michaud | Glycerolipid synthesis and lipid trafficking in plant mitochondria[END_REF]. Non-vesicular lipid transport is thought to occur at membrane contact sites (MCSs), corresponding to particular cell structures formed by the close apposition of two membranes at a distance ≤30nm [START_REF] Michaud | Lipid Trafficking at Membrane Contact Sites During Plant Development and Stress Response[END_REF][START_REF] Petit | Lipids or Proteins : Who Is Leading the Dance at Membrane Contact Sites?[END_REF][START_REF] Scorrano | Coming together to define membrane contact sites[END_REF]. The short distance between the two membranes at MCSs is supposed to decrease the soluble interface that amphiphilic lipid molecules have to cross from the donor to the acceptor membranes. Three types of proteins can be found at MCSs: 1) the tethers, which are proteins able to bridge and maintain the two membranes in close apposition, 2) the effectors, corresponding to proteins providing functionality to the MCSs, and 3) proteins that share both functions [START_REF] Bohnert | Stepping outside the comfort zone of membrane contact site research[END_REF][START_REF] Prinz | The functional universe of membrane contact sites[END_REF][START_REF] Scorrano | Coming together to define membrane contact sites[END_REF]. Beside lipid transport, MCSs play essential roles in many cellular processes including ion exchanges, programmed cell death, organelle division, and appear now as cellular hubs for the regulation of organelle biogenesis and function and cell signaling [START_REF] Michaud | Lipid Trafficking at Membrane Contact Sites During Plant Development and Stress Response[END_REF][START_REF] Prinz | The functional universe of membrane contact sites[END_REF][START_REF] Scorrano | Coming together to define membrane contact sites[END_REF]. Contact sites between many organelles have been observed in plants, but we are just starting to understand their role and importance. Plant MCSs are highly dynamic and regulated during development and in response to many biotic and abiotic stresses [START_REF] Liu | Communications Between the Endoplasmic Reticulum and Other Organelles During Abiotic Stress Response in Plants[END_REF][START_REF] Mathur | Review : Morphology, behaviour and interactions of organelles[END_REF][START_REF] Michaud | Lipid Trafficking at Membrane Contact Sites During Plant Development and Stress Response[END_REF]. In this chapter, we will mainly focus on their role in plant lipid transport. For recent reviews about plant MCSs, see [START_REF] Liu | Communications Between the Endoplasmic Reticulum and Other Organelles During Abiotic Stress Response in Plants[END_REF][START_REF] Michaud | Lipid Trafficking at Membrane Contact Sites During Plant Development and Stress Response[END_REF][START_REF] Mueller-Schuessele | Plastid Transient and Stable Interactions with Other Cell Compartments[END_REF][START_REF] Perez-Sancho | The Arabidopsis synaptotagmin1 is enriched in endoplasmic reticulum-plasma membrane contact sites and confers cellular resistance to mechanical stresses[END_REF][START_REF] Petit | Lipids or Proteins : Who Is Leading the Dance at Membrane Contact Sites?[END_REF].

In plants, lipid transport could virtually occur between all organelles. However, the currently available information about the transported molecules and the mechanisms involved are scarce. By analogy to yeast and animal systems, it can be suspected that huge lipid transport between the ER and mitochondria and the ER and the PM occurs, but direct proofs of such transport and the nature of the transported lipids are still missing [START_REF] Michaud | Glycerolipid synthesis and lipid trafficking in plant mitochondria[END_REF][START_REF] Perez-Sancho | Stitching Organelles : Organization and Function of Specialized Membrane Contact Sites in Plants[END_REF][START_REF] Petrungaro | Lipid exchange at ER-mitochondria contact sites : A puzzle falling into place with quite a few pieces missing[END_REF]Saheki & De Camilli, 2017a). The most investigated non-vesicular lipid trafficking route in plants corresponds to the ER to chloroplast transport of lipid precursors to synthesize plastid lipids. As described above, plastids have the ability to synthesize de novo lipid precursors by the Prokaryotic pathway and to import precursors synthesized in the ER from the Eukaryotic pathway. Due to the specificity of the plastidial and ER sn-2 acyltransferases, glycerolipids arising from both pathways have an acyl-chain signature at the sn-2 position corresponding to a C16 or a C18 for the glycerolipids arising from the Prokaryotic or the Eukaryotic pathways respectively (Figure 1A) [START_REF] Hurlock | Lipid Trafficking in Plant Cells[END_REF][START_REF] Labrant | Lipid transport required to make lipids of photosynthetic membranes[END_REF]. In A. thaliana, around 50% of plastidial lipids come from the Eukaryotic pathway whereas in other plants, like grasses, they almost all arise from this pathway [START_REF] Browse | Fluxes through the prokaryotic and eukaryotic pathways of lipid synthesis in the « 16:3 » plant Arabidopsis thaliana[END_REF][START_REF] Mongrand | The C16:3\C18:3 fatty acid balance in photosynthetic tissues from 468 plant species[END_REF]. Thus, an extensive transfer of lipids from the ER to plastids is required to sustain chloroplast biogenesis. The identity of the transported precursor molecule is still under debate, but it is now widely accepted that different precursors, such as phosphatidylcholine (PC), lyso-PC (i.e. a PC molecule with one acyl-chain), PA or DAG, could be imported into plastids by several co-existing pathways.

The particularity of plant organisms is their ability to adapt to a wide variety of stresses including pathogen attacks, nutrient starvation, extreme temperatures, high light exposure or drought. The modification of plant lipid composition is a widespread phenomenon involved in cell adaptation to stress [START_REF] Liu | Communications Between the Endoplasmic Reticulum and Other Organelles During Abiotic Stress Response in Plants[END_REF]Liu et al., 2019;[START_REF] Michaud | Lipid Trafficking at Membrane Contact Sites During Plant Development and Stress Response[END_REF][START_REF] Moellering | Galactoglycerolipid metabolism under stress : A time for remodeling[END_REF]. The modification of the plant lipidome can play a role in signal transduction by the generation of lipid signaling molecules such as PA, lyso-lipids, free FAs or phosphatidylinositide phosphates (PIPs) [START_REF] Hou | Lipid signalling in plant responses to abiotic stress : Lipid signalling in plant responses to abiotic stress[END_REF]. It can also play a direct role in the adaptation of plant cells to environmental changes, for instance by modifying membrane fluidity during cold or heat stress or by triggering energy storage by the accumulation of triacylglycerols (TAGs) into lipid droplets (LDs) in response to nitrogen starvation (Liu et al., 2019;[START_REF] Meï | Levels of polyunsaturated fatty acids correlate with growth rate in plant cell cultures[END_REF][START_REF] Upchurch | Fatty acid unsaturation, mobilization, and regulation in the response of plants to stress[END_REF]. The best-studied lipid remodeling process occurs in response to phosphate (Pi) starvation, a frequent nutrient stress encountered by plants in nature. Phospholipids retain up to one third of the intracellular Pi content and constitute an important Pi reserve [START_REF] Poirier | A Mutant of Arabidopsis Deficient in Xylem Loading of Phosphate[END_REF]. During Pi starvation, plants partially degrade their phospholipids to remobilize intracellular Pi [START_REF] Plaxton | Metabolic Adaptations of Phosphate-Starved Plants[END_REF][START_REF] Poirier | A Mutant of Arabidopsis Deficient in Xylem Loading of Phosphate[END_REF].

To maintain membrane integrity, the degraded phospholipids are replaced by DGDG [START_REF] Hartel | Galactolipids not associated with the photosynthetic apparatus in phosphate-deprived plants[END_REF][START_REF] Jouhet | Transient increase of phosphatidylcholine in plant cells in response to phosphate deprivation[END_REF][START_REF] Tjellström | Membrane phospholipids as a phosphate reserve : The dynamic nature of phospholipid-to-digalactosyl diacylglycerol exchange in higher plants[END_REF]. Since DGDG is exclusively synthetized in plastids, a massive DGDG export from this organelle to extra-plastidial membranes like vacuole, mitochondria and PM takes place [START_REF] Andersson | Phosphatelimited Oat[END_REF][START_REF] Jouhet | Phosphate deprivation induces transfer of DGDG galactolipid from chloroplast to mitochondria[END_REF]. The transfer of DGDG from plastids to mitochondria is thought to occur by non-vesicular routes at MCSs between the two organelles as their number significantly increases in response to Pi starvation [START_REF] Jouhet | Phosphate deprivation induces transfer of DGDG galactolipid from chloroplast to mitochondria[END_REF]. However, the mechanisms involved in DGDG transport from plastids to vacuoles and PM (i.e. vesicular or nonvesicular) are still unknown.

How does non-vesicular glycerolipid transport occur in plant cells?

The non-vesicular transport of lipids can be divided in three steps: 1) the desorption of the lipid from the donor membrane, 2) its transport through the cytosol and 3) its insertion into the acceptor membrane. The limiting step is the desorption of the lipid from the donor membrane because of the high-energy barrier linked to the extrusion of amphipathic molecules from their hydrophobic environment [START_REF] Somerharju | Is Spontaneous Translocation of Polar Lipids between Cellular Organelles Negligible?[END_REF]. Different mechanisms have been proposed to mediate non-vesicular lipid transport in cells. Spontaneous transport of glycerolipids can occur (Figure 2A), but this process is likely irrelevant in the context of cell division as the half time of spontaneous PC transport in vitro ranges from several hours to days [START_REF] Somerharju | Is Spontaneous Translocation of Polar Lipids between Cellular Organelles Negligible?[END_REF]. Obviously, many factors can influence the rate of spontaneous transport of glycerolipids, including the composition of the donor membrane and the hydrophobicity of the transported molecules (length and unsaturation level of the acyl-chains). For instance, the in vitro spontaneous transfer rate of lysolipids significantly decreases compared to glycerolipids, ranging from seconds to minutes [START_REF] Somerharju | Is Spontaneous Translocation of Polar Lipids between Cellular Organelles Negligible?[END_REF]. It has also been proposed that MCSs might form microdomains with a specific lipid and protein composition favoring non-vesicular lipid transport [START_REF] Gaigg | Characterization of a microsomal subfraction associated with mitochondria of the yeast, Saccharomyces cerevisiae. Involvement in synthesis and import of phospholipids into mitochondria[END_REF][START_REF] Pichler | A subfraction of the yeast endoplasmic reticulum associates with the plasma membrane and has a high capacity to synthesize lipids[END_REF][START_REF] Somerharju | Is Spontaneous Translocation of Polar Lipids between Cellular Organelles Negligible?[END_REF], but this remains to be determined. In vivo, many proteins, such as lipid transfer proteins (LTPs) (Figure 2B-E), as well as multi-subunit complexes that can cross at least two membranes (Figure 2F), are involved in non-vesicular lipid transport. In addition, some membrane proteins can act in concert with LTPs to promote membrane lipid desorption or insertion (Figure 2G). In this chapter, these mechanisms will be discussed in plants. As our current knowledge is scarce, we will rely on the lipid transfer processes described in other organisms to draw a more global picture of the putative mechanisms involved in non-vesicular glycerolipid transport in plant cells.

(Insert Figure 2 here)

Lipid transport mediated by LTPs

LTPs can be divided into different families depending on their structure and mechanism of lipid transport, but they all share common features: 1) they possess a soluble domain with a hydrophobic cavity accommodating one or several lipid molecules, favoring the transport of lipids through soluble compartments, and 2) they are able to significantly increase the rate of glycerolipid transfer between membranes [START_REF] Reinisch | Mechanisms of nonvesicular lipid transport[END_REF][START_REF] Somerharju | Is Spontaneous Translocation of Polar Lipids between Cellular Organelles Negligible?[END_REF][START_REF] Wong | Lipid transfer proteins : The lipid commute via shuttles, bridges and tubes[END_REF]. Some LTPs have also been proposed to directly facilitate membrane lipid desorption or to associate to membrane proteins favoring lipid extrusion [START_REF] Lipp | Lipid Exchangers : Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism[END_REF][START_REF] Reinisch | Mechanisms of nonvesicular lipid transport[END_REF][START_REF] Wong | Lipid transfer proteins : The lipid commute via shuttles, bridges and tubes[END_REF]. Two main mechanisms have been proposed for LTPs: 1) the shuttle mechanism, where the lipid-binding domain of LTPs is able to diffuse through the soluble compartment to shuttle lipids from one membrane to another (Figure 2B-D) and 2) the bridge-like mechanism in which LTPs are able to form hydrophobic tunnels contacting simultaneously two membranes between which lipids will be transported (Figure 2E) [START_REF] Reinisch | Mechanisms of nonvesicular lipid transport[END_REF][START_REF] Wong | Lipid transfer proteins : The lipid commute via shuttles, bridges and tubes[END_REF]. LTPs can be soluble and transiently associated to membranes via protein-lipid or protein-protein interaction (Figure 2B) or anchored to membranes by transmembrane (TM) domains (Figure 2C). Indeed, as further described in this chapter, the lipidbinding domain of LTPs is often associated to additional domains, the most frequent being the pleckstrin-homology (PH) domain, which specifically binds to PIPs, and the C2 domains that can bind a wider range of membrane lipids. These additional domains allow LTPs targeting to particular organelles or MCSs [START_REF] Reinisch | Mechanisms of nonvesicular lipid transport[END_REF][START_REF] Wong | Lipid transfer proteins : The lipid commute via shuttles, bridges and tubes[END_REF]. Furthermore, some LTPs are able to simultaneously bind two membranes and are able to act as lipid transporters and membrane tethers at MCSs (Figure 2D). In plants, a few LTPs has been characterized until know but they are involved in a wide variety of cellular processes beside lipid transport such as lipid signaling, plant resistance to pathogens, adaptation to many abiotic stresses or regulation of gene expression (Table 1).

The SMP family.

The SMP (synaptotagmin-like mitochondrial-lipid binding protein) domain is a lipid binding/transport domain belonging to the TULIPs (tubular lipid binding proteins) superfamily of LTPs [START_REF] Kopec | Homology of SMP domains to the TULIP superfamily of lipid-binding proteins provides a structural basis for lipid exchange between ER and mitochondria[END_REF][START_REF] Wong | Tubular lipid binding proteins (TULIPs) growing everywhere[END_REF]. SMP domain-containing proteins are evolutionary conserved among Eukaryotes [START_REF] Craxton | Synaptotagmin gene content of the sequenced genomes[END_REF][START_REF] Lee | Diverse membrane-associated proteins contain a novel SMP domain[END_REF]. This family has been mostly studied in yeast and mammals and shown to be located at various MCSs: 1) at ER-PM MCSs, for the Extended synaptotagmins (E-Syts), also called Tricalbins in yeast [START_REF] Perez-Sancho | The Arabidopsis synaptotagmin1 is enriched in endoplasmic reticulum-plasma membrane contact sites and confers cellular resistance to mechanical stresses[END_REF]Saheki & De Camilli, 2017b), 2) at ER-mitochondria MCSs, for the ERMES (ER-mitochondria encounter structure) complex subunits in yeast and the PDZD8 protein in mammals [START_REF] Hirabayashi | ER-mitochondria tethering by PDZD8 regulates Ca(2+) dynamics in mammalian neurons[END_REF][START_REF] Kornmann | An ER-mitochondria tethering complex revealed by a synthetic biology screen[END_REF], 3) at ER-Golgi MCSs for Nvj2 in yeast [START_REF] Liu | An inducible ER-Golgi tether facilitates ceramide transport to alleviate lipotoxicity[END_REF] and 4) at the ERendosomes MCSs for PDZD8 [START_REF] Elbaz-Alon | PDZD8 interacts with Protrudin and Rab7 at ER-late endosome membrane contact sites associated with mitochondria[END_REF][START_REF] Shirane | Protrudin and PDZD8 contribute to neuronal integrity by promoting lipid extraction required for endosome maturation[END_REF]. The SMP proteins are mostly predicted to be anchored to membranes by one TM segment linked to the SMP domain by a flexible linker [START_REF] Lee | Diverse membrane-associated proteins contain a novel SMP domain[END_REF]Saheki & De Camilli, 2017b). Other domains can also be associated, as exemplified by C2 domains located in E-Syts allowing the binding of the protein to a second membrane enriched in PIPs (see below). Cristal structures of the SMP domains show that they fold into a β-barrel structure oligomerizing to form hydrophobic tunnels that can accommodate phospholipid molecules [START_REF] Jeong | Crystal structures of Mmm1 and Mdm12-Mmm1 reveal mechanistic insight into phospholipid trafficking at ER-mitochondria contact sites[END_REF]Saheki & De Camilli, 2017b;[START_REF] Schauder | Structure of a lipid-bound extended synaptotagmin indicates a role in lipid transfer[END_REF]. SMP domains are able to form homodimers or heteromultimers [START_REF] Ahyoung | Conserved SMP domains of the ERMES complex bind phospholipids and mediate tether assembly[END_REF][START_REF] Schauder | Structure of a lipid-bound extended synaptotagmin indicates a role in lipid transfer[END_REF]. Analyses of lipids bound to purified proteins as well as in vitro transfer assays support the role of SMP proteins in phospholipid transport between membranes at MCSs, independently of the polar head, suggesting that SMP proteins are non-specific glycerolipid transporters [START_REF] Ahyoung | Conserved SMP domains of the ERMES complex bind phospholipids and mediate tether assembly[END_REF][START_REF] Jeong | Crystal structures of Mmm1 and Mdm12-Mmm1 reveal mechanistic insight into phospholipid trafficking at ER-mitochondria contact sites[END_REF][START_REF] Saheki | Control of plasma membrane lipid homeostasis by the extended synaptotagmins[END_REF]. The flexible linkers located between the TM and the SMP domain of these proteins allow the movement of the lipid binding domain in the cytosol to shuttle lipids from one membrane to another in an ATP-independent manner (Figure 2D) [START_REF] Jeong | Crystal structures of Mmm1 and Mdm12-Mmm1 reveal mechanistic insight into phospholipid trafficking at ER-mitochondria contact sites[END_REF][START_REF] Schauder | Structure of a lipid-bound extended synaptotagmin indicates a role in lipid transfer[END_REF]. By searching in the literature and in domain databases, 13 proteins containing a SMP domain can be identified in A. thaliana (Table 2) [START_REF] Ishikawa | Structural and functional relationships between plasmodesmata and plant endoplasmic reticulum-plasma membrane contact sites consisting of three synaptotagmins[END_REF][START_REF] Perez-Sancho | Stitching Organelles : Organization and Function of Specialized Membrane Contact Sites in Plants[END_REF]. Seven show a domain organization similar to E-Syts and two to Nvj2 proteins.

(Insert Table 2 here) 2.1.1 E-Syts E-Syts contain a TM domain anchoring the protein in the ER, and one or several C2 domains located in the cytosol [START_REF] Perez-Sancho | Stitching Organelles : Organization and Function of Specialized Membrane Contact Sites in Plants[END_REF]Saheki & De Camilli, 2017b). C2 domains are able to bind PIPs-enriched PM in a Ca 2+ -dependent manner, allowing the localization of E-Syts at ER-PM MCSs (Figure 2D). At this junction, E-Syts play a dual role as tethers and lipid transporters [START_REF] Jeyasimman | SMP domain proteins in membrane lipid dynamics[END_REF][START_REF] Saheki | Control of plasma membrane lipid homeostasis by the extended synaptotagmins[END_REF]. Whereas yeast and human genomes contain three E-Syt genes (Reinisch & De Camilli, 2016), this family is expanded in plants, with seven members found in A. thaliana genome (Table 2) [START_REF] Ishikawa | Structural and functional relationships between plasmodesmata and plant endoplasmic reticulum-plasma membrane contact sites consisting of three synaptotagmins[END_REF]. Among this family, Syt1, Syt3, Syt5 and Syt7 (also called AtCLB1) are enriched at ER-PM MCSs and are ubiquitously expressed at a high level [START_REF] De Silva | Arabidopsis thaliana calcium-dependent lipid-binding protein (AtCLB) : A novel repressor of abiotic stress response[END_REF][START_REF] Ishikawa | Structural and functional relationships between plasmodesmata and plant endoplasmic reticulum-plasma membrane contact sites consisting of three synaptotagmins[END_REF][START_REF] Lee | Rare earth elements induce cytoskeleton-dependent and PI4P-associated rearrangement of SYT1/SYT5 endoplasmic reticulum-plasma membrane contact site complexes in Arabidopsis[END_REF]. Intriguingly, Syt7, which binds ceramides, was also observed in the nuclear envelope of root tip cells. Syt7 associates to AtTASH1 promoter to negatively regulate the expression of this gene involved in the synthesis of triterpenoids required for root development [START_REF] De Silva | Arabidopsis thaliana calcium-dependent lipid-binding protein (AtCLB) : A novel repressor of abiotic stress response[END_REF]. The regulation of the localization of this membrane protein to either ER-PM MCSs or the nucleus remains to be investigated. Syt2 is highly expressed in pollen and localized in Golgi and PM [START_REF] Wang | Arabidopsis Synaptotagmin 2 Participates in Pollen Germination and Tube Growth and Is Delivered to Plasma Membrane via Conventional Secretion[END_REF][START_REF] Zhang | Golgi Apparatus-Localized Synaptotagmin 2 Is Required for Unconventional Secretion in Arabidopsis[END_REF]. Syt2 is involved in nonconventional secretion pathways and plays a role in pollen development and pollen tube elongation [START_REF] Wang | Arabidopsis Synaptotagmin 2 Participates in Pollen Germination and Tube Growth and Is Delivered to Plasma Membrane via Conventional Secretion[END_REF][START_REF] Zhang | Golgi Apparatus-Localized Synaptotagmin 2 Is Required for Unconventional Secretion in Arabidopsis[END_REF]. These results show that, in contrast to yeast and mammals, plant E-Syts have a broader subcellular localization and could be involved in the regulation of a wider range of cellular processes besides ER-PM tethering and lipid transport, including gene expression regulation.

The most characterized E-Syt in plants is Syt1 in A. thaliana. Syt1 is anchored in the ER by its N-terminal TM segment and is able to bind negatively charged lipids in the PM via the two C2 domains protruding in the cytosol (Figure 3A) [START_REF] Lee | Rare earth elements induce cytoskeleton-dependent and PI4P-associated rearrangement of SYT1/SYT5 endoplasmic reticulum-plasma membrane contact site complexes in Arabidopsis[END_REF][START_REF] Perez-Sancho | The Arabidopsis synaptotagmin1 is enriched in endoplasmic reticulum-plasma membrane contact sites and confers cellular resistance to mechanical stresses[END_REF][START_REF] Ruiz-Lopez | Synaptotagmins Maintain Diacylglycerol Homeostasis at Endoplasmic Reticulum-Plasma Membrane Contact Sites during Abiotic Stress[END_REF][START_REF] Schapire | Arabidopsis synaptotagmin 1 is required for the maintenance of plasma membrane integrity and cell viability[END_REF][START_REF] Yamazaki | Calcium-dependent freezing tolerance in Arabidopsis involves membrane resealing via synaptotagmin SYT1[END_REF][START_REF] Yamazaki | Arabidopsis synaptotagmin SYT1, a type I signal-anchor protein, requires tandem C2 domains for delivery to the plasma membrane[END_REF]. Whether the PM binding is Ca 2+ dependent or not is still a matter of debate [START_REF] Perez-Sancho | The Arabidopsis synaptotagmin1 is enriched in endoplasmic reticulum-plasma membrane contact sites and confers cellular resistance to mechanical stresses[END_REF][START_REF] Ruiz-Lopez | Synaptotagmins Maintain Diacylglycerol Homeostasis at Endoplasmic Reticulum-Plasma Membrane Contact Sites during Abiotic Stress[END_REF][START_REF] Schapire | Arabidopsis synaptotagmin 1 is required for the maintenance of plasma membrane integrity and cell viability[END_REF]. The localization of Syt1 to ER-PM MCSs also requires VST (VAP-related suppressor of TMM) proteins, which are peripheral PM proteins implicated in stomatal development [START_REF] Ho | Modulators of Stomatal Lineage Signal Transduction Alter Membrane Contact Sites and Reveal Specialization among ERECTA Kinases[END_REF]. Syt1 is involved in many aspects of plant development and biotic and abiotic stress response. Indeed, ER-PM proximity is highly regulated during plant development and in response to different stresses exerting huge constraints on the PM, such as high salinity, osmotic stress, mechanical stress or freezing [START_REF] Ho | Modulators of Stomatal Lineage Signal Transduction Alter Membrane Contact Sites and Reveal Specialization among ERECTA Kinases[END_REF][START_REF] Lee | Ionic stress enhances ER-PM connectivity via phosphoinositideassociated SYT1 contact site expansion in Arabidopsis[END_REF][START_REF] Lee | Rare earth elements induce cytoskeleton-dependent and PI4P-associated rearrangement of SYT1/SYT5 endoplasmic reticulum-plasma membrane contact site complexes in Arabidopsis[END_REF][START_REF] Mcfarlane | Multiscale Structural Analysis of Plant ER-PM Contact Sites[END_REF][START_REF] Perez-Sancho | The Arabidopsis synaptotagmin1 is enriched in endoplasmic reticulum-plasma membrane contact sites and confers cellular resistance to mechanical stresses[END_REF]. In such situations, increasing of ER-PM MCSs is thought to stabilize the PM and to favor its recovery after damages. In accordance with the key role of Syt1 in these processes, 1) Syt1 is overexpressed during cold acclimation or mechanical stress, 2) syt1 mutants are sensitive to freezing, high NaCl concentration, drought, osmotic or mechanical stress and 3) a decrease of PM integrity is observed in syt1 mutants [START_REF] Perez-Sancho | The Arabidopsis synaptotagmin1 is enriched in endoplasmic reticulum-plasma membrane contact sites and confers cellular resistance to mechanical stresses[END_REF][START_REF] Ruiz-Lopez | Synaptotagmins Maintain Diacylglycerol Homeostasis at Endoplasmic Reticulum-Plasma Membrane Contact Sites during Abiotic Stress[END_REF][START_REF] Schapire | Arabidopsis synaptotagmin 1 is required for the maintenance of plasma membrane integrity and cell viability[END_REF][START_REF] Yamazaki | Calcium-dependent freezing tolerance in Arabidopsis involves membrane resealing via synaptotagmin SYT1[END_REF]. Syt1 is also located at ER-PM MCSs close to plasmodesmata (PD) entries. PDs are channels crossing the plant cell wall, ensuring a continuity of PM, ER and cytosol between plant cells and allowing cell-to-cell communication [START_REF] Petit | Lipids or Proteins : Who Is Leading the Dance at Membrane Contact Sites?[END_REF]. In PDs, ER diameter is reduced and ER-PM MCSs mediated by Syt1, as well as by Syt5 and 7, are suspected to play a role in ER constriction to enter and cross PDs [START_REF] Ishikawa | Structural and functional relationships between plasmodesmata and plant endoplasmic reticulum-plasma membrane contact sites consisting of three synaptotagmins[END_REF]. Contrary to what is observed in the case of abiotic stress, syt1 mutants exhibit a higher resistance to fungi and viral infection, notably by reducing pathogen entry into cells or limiting cell-to-cell transmission of viral particles through PDs [START_REF] Ishikawa | Structural and functional relationships between plasmodesmata and plant endoplasmic reticulum-plasma membrane contact sites consisting of three synaptotagmins[END_REF][START_REF] Kim | Synaptotagmin 1 Negatively Controls the Two Distinct Immune Secretory Pathways to Powdery Mildew Fungi in Arabidopsis[END_REF][START_REF] Levy | Synaptotagmin SYTA forms ER-plasma membrane junctions that are recruited to plasmodesmata for plant virus movement[END_REF]. Syt1 is able to interact with three other E-Syts, Syt3, Syt5 and Syt7, suggesting it could also form heteromultimeric complexes at ER-PM MCSs, maybe to promote lipid transfer as in mammals [START_REF] Ishikawa | Structural and functional relationships between plasmodesmata and plant endoplasmic reticulum-plasma membrane contact sites consisting of three synaptotagmins[END_REF][START_REF] Lee | Rare earth elements induce cytoskeleton-dependent and PI4P-associated rearrangement of SYT1/SYT5 endoplasmic reticulum-plasma membrane contact site complexes in Arabidopsis[END_REF][START_REF] Ruiz-Lopez | Synaptotagmins Maintain Diacylglycerol Homeostasis at Endoplasmic Reticulum-Plasma Membrane Contact Sites during Abiotic Stress[END_REF]. Recently, it has been shown that Syt3 has a redundant function with Syt1. Both proteins are involved in ER-PM MCSs formation and are more abundant in these sites during cold stress [START_REF] Ruiz-Lopez | Synaptotagmins Maintain Diacylglycerol Homeostasis at Endoplasmic Reticulum-Plasma Membrane Contact Sites during Abiotic Stress[END_REF]. Interestingly, lipidomic analyses of the double syt1/3 mutant under cold stress show no changes in the whole leaf lipidome but a specific accumulation of DAG and PC in PM fraction, suggesting that DAG clearance from PM is impaired in the double mutant [START_REF] Ruiz-Lopez | Synaptotagmins Maintain Diacylglycerol Homeostasis at Endoplasmic Reticulum-Plasma Membrane Contact Sites during Abiotic Stress[END_REF]. DAG accumulation in PM could be responsible for the cold hypersensitivity of the syt1/3 mutant by altering PM integrity. In addition, Syt1 co-purifies with DAG [START_REF] Ruiz-Lopez | Synaptotagmins Maintain Diacylglycerol Homeostasis at Endoplasmic Reticulum-Plasma Membrane Contact Sites during Abiotic Stress[END_REF], further supporting a role of Syt1, and likely Syt3, in DAG transport at ER-PM MCSs during cold stress (Figure 3A). This first study confirms that, like in yeast and metazoans, E-Syts are involved in both ER-PM tethering and lipid transport, opening important perspectives about the role of these proteins in PM biogenesis and response to stress. Interestingly, five mRNA splice variants were detected for Syt3 [START_REF] Ruiz-Lopez | Synaptotagmins Maintain Diacylglycerol Homeostasis at Endoplasmic Reticulum-Plasma Membrane Contact Sites during Abiotic Stress[END_REF], increasing the putative number of Syts present in plant cells and the functions they can perform.

Other SMP-domain containing proteins.

The localization and role of the six other A. thaliana SMP domain-containing proteins are currently unknown. At1g73200 and At1g17820 have a similar domain organization than yeast Nvj2 with a TM domain separated of the SMP domain by a PH domain (Table 2). Nvj2 is involved in the formation of ER-Golgi contacts and ceramide transport to Golgi to alleviate the ER cytotoxicity linked to ceramide accumulation [START_REF] Liu | An inducible ER-Golgi tether facilitates ceramide transport to alleviate lipotoxicity[END_REF]. At1g73200 is able to restore ceramide transport and ER-Golgi tethering in the yeast Δnvj2 mutant, suggesting that At1g73200 and At1g17820 might be Nvj2 orthologs [START_REF] Liu | An inducible ER-Golgi tether facilitates ceramide transport to alleviate lipotoxicity[END_REF]. The At1g50260 and At3g19830 proteins present an unusual domain organization with four predicted TM domains flanking a SMP and a C2 domain (Table 2). This organization seems to be found only in plants [START_REF] Lee | Diverse membrane-associated proteins contain a novel SMP domain[END_REF]. The At3g60950 and At3g61030 proteins are the only A. thaliana SMP proteins that do not contain a TM domain (Table 2). The SMP domain is associated to a C2 and an endonuclease/exonuclease/phosphatase super family domain that was not found associated to SMP domain in other organisms. No putative orthologs of the ERMES complex subunits or PDZD8, involved in ER-mitochondria and ER-endosomes lipid transport in yeast and mammals respectively, were found in A. thaliana genome.

The StARkin super-family

The StARkin (relatives (kin) of steroidogenic acute regulatory protein (StAR)) is a large superfamily of LTPs that gather families sharing a common lipid binding/transfer domain folding despite a low sequence conservation [START_REF] Hanada | Lipid transfer proteins rectify inter-organelle flux and accurately deliver lipids at membrane contact sites[END_REF][START_REF] Wong | Lipid transfer proteins do their thing anchored at membrane contact sites... But what is their thing?[END_REF]. The StARkin lipid binding/transfer domain is composed of a curved β-sheet containing seven strands and of α-helices that form a hydrophobic cavity accommodating amphiphilic molecules [START_REF] Wong | Lipid transfer proteins do their thing anchored at membrane contact sites... But what is their thing?[END_REF]. StARkin super family includes the StARTs (StAR related transfers), the LAMs (lipid transfer at membrane contact sites), the PITPs (phosphoinositol (PI) transfer proteins), the Ups/PRELI and the Bet-V1 protein family. Bet-V1 (also called PR10) proteins are plant-specific. They are able to bind a wide variety of amphipathic molecules and are involved in the synthesis of many compounds such as flavonoids, alkaloids, sporopollenin or polyphenolics, for instance in response to pathogen infection. As their main substrates are not glycerolipids, this family will not be further described in this chapter (for a recent review about Bet_V1 proteins, see [START_REF] Morris | PR10/Bet v1-like Proteins as Novel Contributors to Plant Biochemical Diversity[END_REF]). PITPs with a StARkin domain play a role in the transport of PI, PC, PA or sphingolipids in different cell compartments and are involved in many cellular processes such as PIPs signaling, vesicular trafficking or sphingolipid synthesis. This family is mainly present in metazoans but is not conserved either in plants or in yeasts and thus will not be further discussed in this chapter (for recent reviews, see [START_REF] Grabon | The interface between phosphatidylinositol transfer protein function and phosphoinositide signaling in higher eukaryotes[END_REF][START_REF] Selitrennik | The role of phosphatidylinositol-transfer proteins at membrane contact sites[END_REF]).

The LAM family

LAM proteins are lipid transporters located at MCSs and conserved throughout the Eukaryotic lineage. All the LAM proteins studied until now are sterol transporters [START_REF] Khafif | Identification and phylogenetic analyses of VASt, an uncharacterized protein domain associated with lipid-binding domains in Eukaryotes[END_REF][START_REF] Wong | Lipid transfer proteins do their thing anchored at membrane contact sites... But what is their thing?[END_REF]. These proteins have a conserved organization with 1) a GRAM (glucosyltransferases, Rab-like GTPase activators and myotubularins) domain, corresponding to a PHlike domain involved in protein/protein or protein/lipid interactions, 2) one or two VASt (VAD1 analog of StAR-related lipid transfer) domains, involved in lipid binding and transport and 3) a Cterminal TM domain [START_REF] Hanada | Lipid transfer proteins rectify inter-organelle flux and accurately deliver lipids at membrane contact sites[END_REF][START_REF] Wong | Lipid transfer proteins do their thing anchored at membrane contact sites... But what is their thing?[END_REF]. The three human LAMs, as well as the yeast Lam1-4 proteins are located at ER-PM MCSs, whereas Lam5 and Lam6 are detected at multiple MCSs in yeast [START_REF] Elbaz-Alon | Lam6 Regulates the Extent of Contacts between Organelles[END_REF][START_REF] Gatta | A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport[END_REF][START_REF] Murley | Ltc1 is an ERlocalized sterol transporter and a component of ER-mitochondria and ER-vacuole contacts[END_REF][START_REF] Sandhu | Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells[END_REF]. They are anchored in the ER by their TM domain but the domains and mechanisms involved in their association with a second organelle remain elusive. Lam6 associates to mitochondria and vacuole through interactions with the protein import receptors Tom70/71 and Vac8 respectively [START_REF] Murley | Ltc1 is an ERlocalized sterol transporter and a component of ER-mitochondria and ER-vacuole contacts[END_REF]. In vitro, the VASt domains of Lam2/4 is able to bind phosphatidylserine (PS)-containing liposomes. The transport efficiency of the VASt domain of GRAMD1 proteins is enhanced by the addition of anionic lipids (PS or PIPs) in the acceptor liposome [START_REF] Horenkamp | Molecular basis for sterol transport by StART-like lipid transfer domains[END_REF][START_REF] Tong | Structural basis of sterol recognition and nonvesicular transport by lipid transfer proteins anchored at membrane contact sites[END_REF], suggesting that the anchoring to a second membrane could also be achieved by interactions of LAMs with lipids. Structural analyses of the VASt domain of several LAM proteins show it is monomeric and folds into a hydrophobic pocket accommodating one sterol molecule [START_REF] Gatta | Structural insights into a StART-like domain in Lam4 and its interaction with sterol ligands[END_REF][START_REF] Horenkamp | Molecular basis for sterol transport by StART-like lipid transfer domains[END_REF]. In vitro, the VASt domain of most of the LAMs is able to bind and transport sterols between membranes in an ATP-independent manner [START_REF] Gatta | A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport[END_REF][START_REF] Gatta | Structural insights into a StART-like domain in Lam4 and its interaction with sterol ligands[END_REF][START_REF] Horenkamp | Molecular basis for sterol transport by StART-like lipid transfer domains[END_REF][START_REF] Murley | Ltc1 is an ERlocalized sterol transporter and a component of ER-mitochondria and ER-vacuole contacts[END_REF]. This transport activity was also confirmed in vivo, where LAM proteins are able to shuttle sterols at ER-PM or ER-vacuole junctions [START_REF] Gatta | A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport[END_REF][START_REF] Murley | Sterol transporters at membrane contact sites regulate TORC1 and TORC2 signaling[END_REF][START_REF] Sandhu | Aster Proteins Facilitate Nonvesicular Plasma Membrane to ER Cholesterol Transport in Mammalian Cells[END_REF]. In yeast, Lam2/4 and Lam6 trigger the formation of sterolenriched microdomains in the PM and in the vacuole respectively, playing a role in signaling during stress response [START_REF] Murley | Ltc1 is an ERlocalized sterol transporter and a component of ER-mitochondria and ER-vacuole contacts[END_REF][START_REF] Murley | Sterol transporters at membrane contact sites regulate TORC1 and TORC2 signaling[END_REF].

A. thaliana genome contains four putative LAM proteins [START_REF] Khafif | Identification and phylogenetic analyses of VASt, an uncharacterized protein domain associated with lipid-binding domains in Eukaryotes[END_REF][START_REF] Wong | Lipid transfer proteins do their thing anchored at membrane contact sites... But what is their thing?[END_REF]. Besides VAD1, plant LAMs have an unusual domain organization compared to yeast and mammals with the presence of additional C2 domains and two TM domains located in the middle of the protein for At1g03370 and At5g50170 (Table 3). The C2 domains might be involved in protein binding to membranes enriched in negatively-charged lipids, such as the PM. Few data are available concerning plant LAMs. VAD1-RFP fusion does not show a punctate pattern and seems to be localized in different cell compartments, including, PM, Golgi, tonoplast, ER, cytosol or nucleus when overexpressed [START_REF] Khafif | An essential role for the VASt domain of the Arabidopsis VAD1 protein in the regulation of defense and cell death in response to pathogens[END_REF]. This localization pattern might be linked to the RFP fused in Cterminal, close to the TM domain, which might alter membrane targeting of VAD1. VAD1 is a negative regulator of the programmed cell death hypersensitive response (HR) occurring in response to pathogen invasion to avoid their propagation in plant tissues [START_REF] Khafif | An essential role for the VASt domain of the Arabidopsis VAD1 protein in the regulation of defense and cell death in response to pathogens[END_REF][START_REF] Lorrain | Vascular associated death1, a novel GRAM domain-containing protein, is a regulator of cell death and defense responses in vascular tissues[END_REF]. Because of its role in cell death regulation, VAD1 is involved in pathogen resistance and the vad1 mutant shows an enhanced resistance to pathogen attack linked to constitutive cell death activation [START_REF] Khafif | An essential role for the VASt domain of the Arabidopsis VAD1 protein in the regulation of defense and cell death in response to pathogens[END_REF][START_REF] Lorrain | Vascular associated death1, a novel GRAM domain-containing protein, is a regulator of cell death and defense responses in vascular tissues[END_REF]. Interestingly, the role of VAD1 in HR, as well as its nuclear localization, are dependent on the VASt, but not on the GRAM domain, suggesting that VAD1 localization and function might be regulated by lipid binding to the VASt domain [START_REF] Khafif | An essential role for the VASt domain of the Arabidopsis VAD1 protein in the regulation of defense and cell death in response to pathogens[END_REF]. The second LAM protein studied in A. thaliana is BAGP1, which also plays a role in biotic stress response by promoting basal immunity against the pathogenic fungus Botrytis cinerea. In response to pathogen infection, BAGP1 interacts with the protease APCB1 to promote the cleavage of BAG6 (Bcl2-associated athanogene), an autophagy activator inducing basal immunity against fungi (Li et al., 2016). However, the localization of BAGP1, how it regulates BAG6 cleavage and whether lipids are involved in the regulation of its function are still unknown. Overall, LAM proteins seem to play important roles in biotic stress response in plants, but despite their homology with yeast and mammalian LAMs, their localization and their ability to bind and/or transport lipids remain to be determined.

(Insert Table 3 here)

The Ups/PRELI family

Proteins of the Ups/PRELI family are soluble proteins located in the intermembrane space (IMS) of mitochondria acting in heterodimers with the molecular chaperone Mdm35/TRIAP1 to shuttle lipids from the outer (OM) to the inner (IM) membrane. Three Ups/PRELI and one Mdm35/TRIAP1 proteins exist in yeast (Ups1-3, Mdm35) and mammals (PRELID1, PRELID3a, PRELID3b, TRIAP1). The Ups1/PRELID1 and Ups2/PRELID3b proteins regulate mitochondrial CL and PE metabolism respectively by promoting the transport of lipid substrates, PA and PS respectively, from the OM to the IM where cardiolipin (CL) and phosphatidylethanolamine (PE) synthesizing enzymes are located [START_REF] Aaltonen | MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria[END_REF][START_REF] Connerth | Intramitochondrial Transport of Phosphatidic Acid in Yeast by a Lipid Transfer Protein[END_REF][START_REF] Miyata | Phosphatidylserine transport by Ups2-Mdm35 in respiration-active mitochondria[END_REF][START_REF] Osman | The genetic interactome of prohibitins : Coordinated control of cardiolipin and phosphatidylethanolamine by conserved regulators in mitochondria[END_REF]. Mdm35/TRIAP1 acts as a chaperone facilitating import and stability of Ups/PRELI proteins in the IMS [START_REF] Potting | Regulation of mitochondrial phospholipids by Ups1/PRELI-like proteins depends on proteolysis and Mdm35[END_REF][START_REF] Potting | TRIAP1/PRELI Complexes Prevent Apoptosis by Mediating Intramitochondrial Transport of Phosphatidic Acid[END_REF]. Mdm35/TRIAP1 dissociates from Ups/PRELI upon binding to membrane enriched in anionic lipids, such as CL, allowing lipid releasing and protein recycling [START_REF] Aaltonen | MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria[END_REF][START_REF] Connerth | Intramitochondrial Transport of Phosphatidic Acid in Yeast by a Lipid Transfer Protein[END_REF][START_REF] Watanabe | Structural and mechanistic insights into phospholipid transfer by Ups1-Mdm35 in mitochondria[END_REF]. The Ups/PRELI proteins fold is characteristic of the StARkin domain superfamily with a seven-stranded β-sheet decorated with three flexible helices forming a hydrophobic cavity [START_REF] Miliara | Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins[END_REF][START_REF] Watanabe | Structural and mechanistic insights into phospholipid transfer by Ups1-Mdm35 in mitochondria[END_REF]. Interestingly, in plants, only one Ups/PRELI (At5g13070) and one Mdm35/TRIAP1 (At4g33100) homologs are found [START_REF] Wideman | The evolution of ERMIONE in mitochondrial biogenesis and lipid homeostasis : An evolutionary view from comparative cell biology[END_REF]. At5g13070 protein is uncharacterized in A. thaliana but is predicted to be located in mitochondria IMS [START_REF] Hooper | SUBA4 : The interactive data analysis centre for Arabidopsis subcellular protein locations[END_REF][START_REF] Schwacke | ARAMEMNON, a novel database for Arabidopsis integral membrane proteins[END_REF]. Sequence analysis suggests that At5g13070 is closer to the Ups2 than the Ups1 family, and might transport PS because of the absence of a conserved lysine residue (K58), present in Ups1 family, which impaired PS transport [START_REF] Miliara | Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins[END_REF][START_REF] Wideman | The evolution of ERMIONE in mitochondrial biogenesis and lipid homeostasis : An evolutionary view from comparative cell biology[END_REF]. In vitro, yeast Ups2 can also transport PA, but in vivo, no decrease of CL is observed in Δups2 showing that Ups2 does not play an essential role in PA transport [START_REF] Miyata | Phosphatidylserine transport by Ups2-Mdm35 in respiration-active mitochondria[END_REF][START_REF] Osman | The genetic interactome of prohibitins : Coordinated control of cardiolipin and phosphatidylethanolamine by conserved regulators in mitochondria[END_REF]. Thus, the plant Ups/PRELI protein might be involved in the transport of both PS and PA and/or alternative pathways might exist to transport PA for CL synthesis in the IM.

The StART family

StART domain-containing proteins are conserved throughout evolution [START_REF] Ponting | START : A lipid-binding domain in StAR, HD-ZIP and signalling proteins[END_REF]. StART family is expanded in higher plants with 35 and 29 members in A. thaliana and in rice respectively whereas 15 members are found in humans and only one in yeast [START_REF] Clark | The START-domain proteins in intracellular lipid transport and beyond[END_REF][START_REF] Schrick | START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors[END_REF]. StART proteins are divided into subfamilies according to their domain organization and lipid binding specificity [START_REF] Clark | The START-domain proteins in intracellular lipid transport and beyond[END_REF][START_REF] Schrick | START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors[END_REF]. They are able to bind different ligands such as sterols, ceramides or phospholipids [START_REF] Clark | The START-domain proteins in intracellular lipid transport and beyond[END_REF]. As only members of the StARD2 subfamily have been shown to transport phospholipids [START_REF] Kang | PC-TP/StARD2 : Of membranes and metabolism[END_REF], we will focus on this subfamily (for reviews about StART proteins, see [START_REF] Clark | The mammalian START domain protein family in lipid transport in health and disease[END_REF][START_REF] Clark | The START-domain proteins in intracellular lipid transport and beyond[END_REF]). In humans, there are three phospholipidbinding StART proteins (StARD2, StARD7 and StARD10) also called PC-TPs (PC transporter proteins), which are small proteins (around 200-300 aa) only composed of a StART domain [START_REF] Clark | The START-domain proteins in intracellular lipid transport and beyond[END_REF][START_REF] Schrick | START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors[END_REF]. StARD2 binds and transports PC between liposomes in vitro [START_REF] Wirtz | Phospholipid transfer proteins[END_REF]. It folds into a nine-stranded curved β-sheet with four helices forming a binding pocket accommodating one PC molecule [START_REF] Roderick | Structure of human phosphatidylcholine transfer protein in complex with its ligand[END_REF]. This protein is localized in the cytosol and the nucleus and has been shown to regulate lipid droplet (LD) size in rat liver as well as the interplay between glucose and lipid metabolism [START_REF] Clark | The START-domain proteins in intracellular lipid transport and beyond[END_REF][START_REF] Kang | PC-TP/StARD2 : Of membranes and metabolism[END_REF][START_REF] Kanno | Interacting Proteins Dictate Function of the Minimal START Domain Phosphatidylcholine Transfer Protein/StarD2[END_REF][START_REF] Nicholls | Phosphatidylcholine transfer protein/StarD2 promotes microvesicular steatosis and liver injury in murine experimental steatohepatitis[END_REF]. In the nucleus, StARD2 also interacts with the Homeodomain (HD) transcription factor Pax3, involved in tissues and organs development [START_REF] Buckingham | The role of Pax genes in the development of tissues and organs : Pax3 and Pax7 regulate muscle progenitor cell functions[END_REF], and stimulates its activity [START_REF] Kang | PC-TP/StARD2 : Of membranes and metabolism[END_REF][START_REF] Kanno | Interacting Proteins Dictate Function of the Minimal START Domain Phosphatidylcholine Transfer Protein/StarD2[END_REF]. Thus, it seems that StARD2 is more likely a PC-sensor regulating different cellular pathways than a PC transporter between membranes. In contrast, StARD7 is involved in PC transport from the mitochondrial OM to the IM in mammals [START_REF] Horibata | StarD7 Protein Deficiency Adversely Affects the Phosphatidylcholine Composition, Respiratory Activity, and Cristae Structure of Mitochondria[END_REF][START_REF] Saita | PARL partitions the lipid transfer protein STARD7 between the cytosol and mitochondria[END_REF]. Stard7 KO or KD cell lines present a variety of mitochondrial defects including a reduced respiration rate and ATP level, mtDNA damages and defects in mitochondrial cristae structure, highlighting the importance of this PC-transporter for mitochondria biogenesis and functions [START_REF] Flores-Martín | Suppression of StarD7 promotes endoplasmic reticulum stress and induces ROS production[END_REF][START_REF] Horibata | StarD7 Protein Deficiency Adversely Affects the Phosphatidylcholine Composition, Respiratory Activity, and Cristae Structure of Mitochondria[END_REF][START_REF] Saita | PARL partitions the lipid transfer protein STARD7 between the cytosol and mitochondria[END_REF][START_REF] Yang | The Phosphatidylcholine Transfer Protein Stard7 is Required for Mitochondrial and Epithelial Cell Homeostasis[END_REF]. Two isoforms, StARD7-I, with a 75aa N-terminal mitochondrial targeting sequence, and StARD7-II, co-exist in cells and are able to bind PC and ceramides, but only PC is transported between liposomes [START_REF] Bockelmann | A search for ceramide binding proteins using bifunctional lipid analogs yields CERT-related protein StarD7[END_REF][START_REF] Horibata | StarD7 mediates the intracellular trafficking of phosphatidylcholine to mitochondria[END_REF][START_REF] Saita | PARL partitions the lipid transfer protein STARD7 between the cytosol and mitochondria[END_REF]. StARD10 is able to bind and transport PC and PE in vitro and its transport activity is inhibited by phosphorylation, showing that lipid transfer and membrane binding can be regulated by post-translational modifications [START_REF] Olayioye | StarD10, a START Domain Protein Overexpressed in Breast Cancer, Functions as a Phospholipid Transfer Protein[END_REF][START_REF] Olayioye | Phosphorylation of StarD10 on Serine 284 by Casein Kinase II Modulates Its Lipid Transfer Activity[END_REF]. In lung alveolar type II epithelial cells, StARD10 interacts with the ER lyso-PC acyltransferase 1 (LPCAT1) and promotes lipid transport on lamellar bodies (LB) where lipids are stored until secretion in the lung surfactant [START_REF] Goss | Regulation of lung surfactant phospholipid synthesis and metabolism[END_REF][START_REF] Lin | Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) Specifically Interacts with Phospholipid Transfer Protein StarD10 to Facilitate Surfactant Phospholipid Trafficking in Alveolar Type II Cells[END_REF].

Six homologs of the PC-PT family can be found in A. thaliana (Table 4). They are longer than their yeast and human counterparts (around 400aa) and predicted to possess one or several TM domains [START_REF] Schrick | START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors[END_REF]. TM domain-containing StART proteins are also found in rice and chickpea [START_REF] Satheesh | Transmembrane START domain proteins : In silico identification, characterization and expression analysis under stress conditions in chickpea (Cicer arietinum L.)[END_REF][START_REF] Schrick | START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors[END_REF]. They are expressed at different stages of plant development and expression of some of them are induced or repressed in response to biotic or abiotic stress [START_REF] Satheesh | Transmembrane START domain proteins : In silico identification, characterization and expression analysis under stress conditions in chickpea (Cicer arietinum L.)[END_REF]. Information about the function, localization and lipid binding properties of these proteins is scarce. 3D homology modeling of the At3g13062 shows that the StART domain overlaps with the crystal structure of StARD2 despite a low primary sequence similarity [START_REF] Schrick | START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors[END_REF]. None of them is predicted to be targeted in mitochondria, questioning the existence of a StARD7 homolog in plants. Concerning the other StART domain-containing proteins, five members in A. thaliana have in C-terminal a domain of unknown function (DUF1336), which is plant-specific (Table 4) [START_REF] Schrick | START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors[END_REF]. One member, EDR2, is a negative regulator of cell death during pathogen attack and binds to PI-4-monophosphate (PI(4)P) via its PH domain [START_REF] Vorwerk | EDR2 negatively regulates salicylic acid-based defenses and cell death during powdery mildew infections of Arabidopsis thaliana[END_REF], but the role of PI(4)P binding or of the StART domain has not been further investigated. It has to be noted that plants possess a unique subfamily of transcription factors composed of a StART domain associated to an homeodomain (HD) (21 members in A. thaliana, Table 4) [START_REF] Schrick | START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors[END_REF]. In accordance with their putative role in the regulation of gene expression, they are predicted to be located in the nucleus and this localization was confirmed for some of them [START_REF] Khosla | HD-Zip Proteins GL2 and HDG11 Have Redundant Functions in Arabidopsis Trichomes, and GL2 Activates a Positive Feedback Loop via MYB23[END_REF]Lee et al., 2006;[START_REF] Schrick | Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity[END_REF]. Mutant analyses highlighted the importance of these transcription factors in plant development [START_REF] Schrick | Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity[END_REF]. However, the role of the StART domains in the regulation of plant development, as well as their ligands, are still poorly understood. The StART domain of Glabra 2 (GL2), is required for the function of this transcription factor but not for its nuclear localization [START_REF] Schrick | Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity[END_REF]. Interestingly, the StART domain of the mouse cholesterol transporter StAR can functionally replace GL2 StART domain and a mutation affecting StAR cholesterol binding site prevents functional complementation, indicating that sterol binding to GL2 is required for its transcriptional activator function [START_REF] Schrick | Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity[END_REF]. In the same study, the authors analyzed the metabolites associated to the StART domain of three A. thaliana proteins (GL2, PDF2 and At3g13062) expressed and purified from yeast cells. Most of the detected metabolites are lipids. GL2 and PDF2 are associated to similar metabolites including lyso-PC, PC, DAG or sphingolipids whereas the putative PC-PT At3g13062 was associated to DAG and TAG [START_REF] Schrick | Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity[END_REF]. However, because the study was performed in yeast, which contains only one sort of sterol (ergosterol) and missed some plant-specific lipids such as galactoglycerolipids, the lipid-binding ability of these A. thaliana StART domains might be misevaluated. Because of the association of a StARkin with a HD domain, regulation of gene expression by these plant-specific transcription factors might involve lipid binding.

(Insert Table 4 here)

ORP

ORPs (Oxysterol-binding protein (OSBP) related proteins), also called Osh (Oxysterol-binding protein homolog), are a widespread family of LTPs that regulate sterol and phospholipid homeostasis [START_REF] Lipp | Lipid Exchangers : Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism[END_REF][START_REF] Moser Von Filseck | Running up that hill : How to create cellular lipid gradients by lipid counter-flows[END_REF][START_REF] Pietrangelo | Bridging the molecular and biological functions of the oxysterol-binding protein family[END_REF][START_REF] Santos | ORP5 and ORP8 : Sterol Sensors and Phospholipid Transfer Proteins at Membrane Contact Sites?[END_REF]. Twelve and seven homologs are found in human and yeast genomes respectively and most of them are located at MCSs and are able to bind and transport sterols and PIPs between different organelles [START_REF] Moser Von Filseck | Running up that hill : How to create cellular lipid gradients by lipid counter-flows[END_REF][START_REF] Pietrangelo | Bridging the molecular and biological functions of the oxysterol-binding protein family[END_REF][START_REF] Schulz | Sterol transport in yeast and the oxysterol binding protein homologue (OSH) family[END_REF]. Some of them, Osh6/7 in yeast and their homologs in human ORP5/8, are also able to bind and transport PS and will be further described below [START_REF] Lipp | Lipid Exchangers : Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism[END_REF][START_REF] Santos | ORP5 and ORP8 : Sterol Sensors and Phospholipid Transfer Proteins at Membrane Contact Sites?[END_REF]. ORP proteins all contain an ORD (oxysterol-binding related domain), which folds into a hydrophobic β-barrel accommodating one lipid molecule with a flexible N-terminal lid that regulates the opening/closing of the tunnel entry [START_REF] Dong | The crystal structure of ORP3 reveals the conservative PI4P binding pattern[END_REF][START_REF] Im | Structural mechanism for sterol sensing and transport by OSBP-related proteins[END_REF][START_REF] Maeda | Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins[END_REF]. The ORD domain can be associated to other domains regulating membrane binding and protein sub-cellular localization, such as a PH domain, a FFAT (Phenylalanine-Phenylalanine Acidic Track) motif targeting proteins to ER, or a TM domain [START_REF] Pietrangelo | Bridging the molecular and biological functions of the oxysterol-binding protein family[END_REF][START_REF] Schulz | Sterol transport in yeast and the oxysterol binding protein homologue (OSH) family[END_REF]. Interestingly, some of them (ORP5/8 and OSBP in human and Osh4/6/7 in yeast) use an original counter-exchange mechanism to transport lipids from one membrane to another against their concentration gradient [START_REF] Chung | PI4P/phosphatidylserine countertransport at ORP5-and ORP8-mediated ER-plasma membrane contacts[END_REF][START_REF] De Saint-Jean | Osh4p exchanges sterols for phosphatidylinositol 4-phosphate between lipid bilayers[END_REF][START_REF] Lipp | Lipid Exchangers : Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism[END_REF][START_REF] Moser Von Filseck | Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4phosphate[END_REF][START_REF] Moser Von Filseck | Running up that hill : How to create cellular lipid gradients by lipid counter-flows[END_REF]. Osh6/7 and ORP5/8 are located at ER-PM MCSs where they play a role in PS transport to PM, PS being enriched in the cytosolic leaflet. Those proteins are able to bind PS or PI(4)P, which are abundant in the PM, by their ORD domain in a mutually exclusive manner [START_REF] Maeda | Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins[END_REF][START_REF] Moser Von Filseck | Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4phosphate[END_REF]. In vivo, Osh6/7 and ORP5/8 extract PS from its site of synthesis, the ER, to shuttle and release it into the PM where PI(4)P is extracted and shuttled back to the ER [START_REF] Maeda | Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins[END_REF][START_REF] Moser Von Filseck | Phosphatidylserine transport by ORP/Osh proteins is driven by phosphatidylinositol 4phosphate[END_REF]. The hydrolysis of PI(4)P by the ER phosphatase Sac1 is suspected to provide sufficient energy for PS transport and to maintain low PI(4)P content in the ER compared to PM, favoring directional PS transport [START_REF] Lipp | Lipid Exchangers : Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism[END_REF][START_REF] Moser Von Filseck | Running up that hill : How to create cellular lipid gradients by lipid counter-flows[END_REF]. Interestingly, ORP5/8 are also located at ER-mitochondria and ER-LD MCSs. ORP5 interacts with LD via an amphipathic helix in the ORP domain and has been shown to regulate LD PS and PI(4)P content and LD size [START_REF] Du | ORP5 localizes to ER-lipid droplet contacts and regulates the level of PI(4)P on lipid droplets[END_REF]. At ER-mitochondria MCSs, ORP5 and ORP8 interact with each other and with PTPIP51, an OM protein involved in mitochondria-ER tethering via its interaction with the ER protein VAP-B [START_REF] Galmes | ORP5/ORP8 localize to endoplasmic reticulum-mitochondria contacts and are involved in mitochondrial function[END_REF][START_REF] Stoica | ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43[END_REF]. ORP5/8 are involved in PS transport at ERmitochondria to fulfill PE synthesis in the IM by PSD1 [START_REF] Galmes | ORP5/ORP8 localize to endoplasmic reticulum-mitochondria contacts and are involved in mitochondrial function[END_REF][START_REF] Rochin | ORP5 Transfers Phosphatidylserine To Mitochondria And Regulates Mitochondrial Calcium Uptake At Endoplasmic Reticulum-Mitochondria Contact Sites[END_REF]. Interestingly, most of the ORP5 proteins located at ER-mitochondria MCSs are close to cristae junctions (CJ), which are OM-IM MCSs maintained by the IM MICOS complex [START_REF] Mukherjee | MICOS and the mitochondrial inner membrane morphology -when things get out of shape[END_REF][START_REF] Rochin | ORP5 Transfers Phosphatidylserine To Mitochondria And Regulates Mitochondrial Calcium Uptake At Endoplasmic Reticulum-Mitochondria Contact Sites[END_REF], suggesting that ORP5/8 might link PS transport from ER to the mitochondrial IM. As PIPs are barely detected in mitochondria, the transport of PS might be directed by a concentration gradient of PS rather than by a counter-exchange mechanism. In addition to its role in PS transport to mitochondria and PM, ORP5 is also involved in cholesterol transfer from low density lipoproteins (LDL) to late endosomes/lysosomes in Niemann Pick C (NPC) fibroblasts [START_REF] Du | A role for oxysterol-binding protein-related protein 5 in endosomal cholesterol trafficking[END_REF] and regulates Ca 2+ accumulation in the mitochondria and in the PM microdomains called caveolae [START_REF] Pulli | Oxysterol-binding protein related-proteins (ORPs) 5 and 8 regulate calcium signaling at specific cell compartments[END_REF][START_REF] Rochin | ORP5 Transfers Phosphatidylserine To Mitochondria And Regulates Mitochondrial Calcium Uptake At Endoplasmic Reticulum-Mitochondria Contact Sites[END_REF]. This example shows the versatility of functions and localizations associated to ORP proteins.

A. thaliana and rice genomes encode twelve and six ORP domain-containing proteins, respectively [START_REF] Skirpan | Identification and characterization of PiORP1, a Petunia oxysterol-binding-protein related protein involved in receptor-kinase mediated signaling in pollen, and analysis of the ORP gene family in Arabidopsis[END_REF][START_REF] Umate | Oxysterol binding proteins (OSBPs) and their encoding genes in Arabidopsis and rice[END_REF][START_REF] Ye | Membrane Contact Sites and Organelles Interaction in Plant Autophagy[END_REF]. A. thaliana proteins cluster in four groups and five proteins contain a PH domain and a FFAT motif that might be involved in their localization to ER and endomembrane compartments whereas the other members only have an ORD domain (Table 5) [START_REF] Ye | Membrane Contact Sites and Organelles Interaction in Plant Autophagy[END_REF]. Interestingly, when phylogeny analyses are performed with yeast and mammalian proteins, no A. thaliana proteins group with the PS transfer proteins ORP5/8 and Osh6/7 [START_REF] Skirpan | Identification and characterization of PiORP1, a Petunia oxysterol-binding-protein related protein involved in receptor-kinase mediated signaling in pollen, and analysis of the ORP gene family in Arabidopsis[END_REF][START_REF] Ye | Membrane Contact Sites and Organelles Interaction in Plant Autophagy[END_REF], suggesting that ORP proteins might not transport PS in plants or that this transport is mediated by a more distantly related family of ORPs. All ORPs are expressed in different tissues and developmental stages, ORP3 group being the most highly expressed [START_REF] Skirpan | Identification and characterization of PiORP1, a Petunia oxysterol-binding-protein related protein involved in receptor-kinase mediated signaling in pollen, and analysis of the ORP gene family in Arabidopsis[END_REF][START_REF] Umate | Oxysterol binding proteins (OSBPs) and their encoding genes in Arabidopsis and rice[END_REF]. Most of the ORPs genes are induced by biotic and/or abiotic stress as well as in response to toxic compounds such as metals [START_REF] Umate | Oxysterol binding proteins (OSBPs) and their encoding genes in Arabidopsis and rice[END_REF]. In accordance with this, GmOSBP is highly induced during high salt stress and senescence and its PH domain targets GFP protein to the nucleus in onion epidermal cells, suggesting the protein might be involved in gene expression regulation in soybean [START_REF] Li | Molecular characterization of a novel salt-inducible gene for an OSBP (oxysterol-binding protein)-homologue from soybean[END_REF]. In petunia, PiORP1 is highly expressed in pollen tubes where it interacts with the receptor-like kinase PRK1, a protein essential for pollen tube development, leading to PiORP1 phosphorylation [START_REF] Skirpan | Identification and characterization of PiORP1, a Petunia oxysterol-binding-protein related protein involved in receptor-kinase mediated signaling in pollen, and analysis of the ORP gene family in Arabidopsis[END_REF]. PiORP1-GFP localizes in the cytosol and forms PH domain-dependent punctates in the PM, suggesting a localization at PM MCSs. However, the lipid binding specificity of PiORP1 and its role in pollen tube development, maybe to provide lipids to PM for elongation, is still unknown. In A. thaliana, ORP3A is localized in the ER via a WFDE motif required for its interaction with the ER VAP protein PVA12 [START_REF] Saravanan | The targeting of the oxysterol-binding protein ORP3a to the endoplasmic reticulum relies on the plant VAP33 homolog PVA12[END_REF]. When this interaction is disrupted, ORP3A localizes to the Golgi compartment. In vitro, ORP3A ORD domain binds sitosterols but PVA12 interaction as well as the ER localization of ORP3A are independent of its ability to bind lipids [START_REF] Saravanan | The targeting of the oxysterol-binding protein ORP3a to the endoplasmic reticulum relies on the plant VAP33 homolog PVA12[END_REF]. All these results suggest that ORP3A could shuttle sitosterol from ER to Golgi (Figure 3B). Plants ORP proteins could also be involved in the replication of some viruses that require specific lipids or membrane compartments for replication [START_REF] Barajas | Coopted oxysterol-binding ORP and VAP proteins channel sterols to RNA virus replication sites via membrane contact sites[END_REF][START_REF] Nagy | Viral sensing of the subcellular environment regulates the assembly of new viral replicase complexes during the course of infection[END_REF][START_REF] Rodriguez-Peña | Changes in Subcellular Localization of Host Proteins Induced by Plant Viruses[END_REF]. For instance, the bushy stunt virus (TBSV), a plant (+)RNA virus belonging to the Tombusvirus family, induces the formation of specific compartments arising from peroxisome membrane invagination, called spherules. Within spherules the assembly of the virus replicase complex (VRC) and the replication process occur, protected from degradation [START_REF] Nagy | Host factors with regulatory roles in tombusvirus replication[END_REF][START_REF] Rodriguez-Peña | Changes in Subcellular Localization of Host Proteins Induced by Plant Viruses[END_REF]. The TBSV protein p33 is involved in the recruitment of the VRC to peroxisome membrane. Using a yeast model system to investigate the mechanism of TBSV replication, it has been shown that sterols are redistributed from the PM to the virus replication site and that sterols are essential for efficient replication of the virus [START_REF] Barajas | Coopted oxysterol-binding ORP and VAP proteins channel sterols to RNA virus replication sites via membrane contact sites[END_REF]. Interestingly, p33 interacts with six A. thaliana ORPs (ORP3A-C and ORP4A-C) as well as with five VAP proteins and ORP3A and PVA12 have been shown to co-localize with p33 close to VRCs in Nicotiana benthamiana [START_REF] Barajas | Coopted oxysterol-binding ORP and VAP proteins channel sterols to RNA virus replication sites via membrane contact sites[END_REF]. In both yeast and plant systems, the presence of a replicative TBSV virus induces ER-peroxisomes MCSs formation close to spherules, p33 being located in both peroxisomes and ER membranes [START_REF] Barajas | Coopted oxysterol-binding ORP and VAP proteins channel sterols to RNA virus replication sites via membrane contact sites[END_REF]. This suggests that p33 induces peroxisome-ER MCSs formation and recruits ORP proteins to promote sterol transfer from ER to peroxisomes and to stimulate TBSV replication and spherule formation.

(Insert Table 5 here) 2.4 VPS13-like protein family / Chorein_N domain-containing proteins VPS13-like proteins are highly conserved from yeast to human. This protein family is composed of two main protein types: the huge (>3000 aa) vacuolar protein sorting 13 (VPS13) and the autophagy-related 2 (ATG2) proteins. Among all the functional domains found in VPS13-like proteins, the N-terminal Chorein_N domain and the adjacent VPS13_N domain, both involved in lipid binding are the best conserved [START_REF] De | The Vps13p-Cdc31p complex is directly required for TGN late endosome transport and TGN homotypic fusion[END_REF][START_REF] Pfisterer | Lipid droplet and early autophagosomal membrane targeting of Atg2A and Atg14L in human tumor cells[END_REF]. In VPS13 proteins, these domains are usually followed by a long region containing repeating coiled regions and the characteristic Vps13 adaptor binding (VAB) domain. Their C-terminus is typically composed of an APT1-homology domain, an ATG-homology domain (ATG_C) and finally a C-terminal PH domain. Most of these domains are involved in the subcellular targeting of VPS13 proteins [START_REF] Dziurdzik | The Vps13 Family of Lipid Transporters and Its Role at Membrane Contact Sites[END_REF]. VPS13-like proteins associate to membranes and MCSs and are implicated in a large variety of cellular processes like sporulation and trans-Golgi network homotypic fusion in yeast [START_REF] De | The Vps13p-Cdc31p complex is directly required for TGN late endosome transport and TGN homotypic fusion[END_REF][START_REF] Park | VPS13 regulates membrane morphogenesis during sporulation in Saccharomyces cerevisiae[END_REF][START_REF] Rabitsch | A screen for genes required for meiosis and spore formation based on whole-genome expression[END_REF] or regulation of autophagy, cytoskeletal architecture and cell survival in humans [START_REF] Föller | Chorein-sensitive polymerization of cortical actin and suicidal cell death in chorea-acanthocytosis[END_REF][START_REF] Muñoz-Braceras | TipC and the chorea-acanthocytosis protein VPS13A regulate autophagy in Dictyostelium and human HeLa cells[END_REF]. The Saccharomyces cerevisiae genome contains only one VPS13 protein, which localizes to nuclear-vacuolar junctions, mitochondriaendosome and vacuole-mitochondria MCSs depending on the cell physiological condition [START_REF] Bean | Competitive organelle-specific adaptors recruit Vps13 to membrane contact sites[END_REF]. Four homologs have been identified in human which also localize to different MCSs (for recent review, see [START_REF] Dziurdzik | The Vps13 Family of Lipid Transporters and Its Role at Membrane Contact Sites[END_REF]). Yeast and human genomes encode one and two ATG2 protein respectively, that are localized to ER-autophagosome MCSs [START_REF] Graef | ER exit sites are physical and functional core autophagosome biogenesis components[END_REF][START_REF] Suzuki | Fine mapping of autophagy-related proteins during autophagosome formation in Saccharomyces cerevisiae[END_REF] and are part of the autophagosome forming machinery [START_REF] Nakatogawa | Mechanisms governing autophagosome biogenesis[END_REF]. Both VPS13 and ATG2 proteins play a major role in lipid transport. In vitro, the N-terminal parts of Chaetomium thermophilum VPS13 and human ATG2A are able to bind at least 10 glycerolipids and to transport them between liposomes, strongly suggesting they are non-specific glycerolipid transporters [START_REF] Kumar | VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites[END_REF][START_REF] Valverde | ATG2 transports lipids to promote autophagosome biogenesis[END_REF]. Structural analyses show that the N-terminal extremity containing the Chorein_N domain forms a scoop-like hydrophobic cavity that could presumably accommodate glycerolipids and that is extended by a long hydrophobic groove with a rod-like β-strand structure [START_REF] Kumar | VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites[END_REF][START_REF] Li | Cryo-EM reconstruction of a VPS13 fragment reveals a long groove to channel lipids between membranes[END_REF][START_REF] Osawa | Atg2 mediates direct lipid transfer between membranes for autophagosome formation[END_REF][START_REF] Valverde | ATG2 transports lipids to promote autophagosome biogenesis[END_REF]. Due to their localization at MCSs, their lipid-friendly elongated groove structure and their size exceeding 20 nm [START_REF] De | The Vps13p-Cdc31p complex is directly required for TGN late endosome transport and TGN homotypic fusion[END_REF], it has been broadly hypothesized that VPS13 proteins form bridges between membranes at MCSs to mediate non-specific bulk glycerolipid transport by a bridge-like mechanism (Figure 2E) [START_REF] Dziurdzik | The Vps13 Family of Lipid Transporters and Its Role at Membrane Contact Sites[END_REF][START_REF] Kumar | VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites[END_REF][START_REF] Li | Cryo-EM reconstruction of a VPS13 fragment reveals a long groove to channel lipids between membranes[END_REF][START_REF] Reinisch | Mechanisms of nonvesicular lipid transport[END_REF].

Nothing is known about VPS13-like plant homologs. In A. thaliana, five Chorein_N domaincontaining proteins have been identified, three of which have already been previously identified (Table 6) [START_REF] Michaud | Glycerolipid synthesis and lipid trafficking in plant mitochondria[END_REF][START_REF] Velayos-Baeza | Analysis of the human VPS13 gene family[END_REF]. Three unknown proteins (At4g17140, At1g48090 and At5g24740) harbor the typical VPS13 protein conserved domains, especially the Chorein_N domain and the VPS13_N domain present at their N-terminal extremity. Given the high degree of homology found with other VPS13 proteins, we propose to rename At4g17140, At1g48090 and At5g24740 respectively AtVPS13A, AtVPS13B and AtVPS13C. Currently, nothing is known about AtVPS13A-C cellular localization. Predictions suggest a localization in the Golgi for all three proteins. Surprisingly, AtVPS13A and AtVPS13B have an additional VPS62-homology domain of unknown function in the middle of the protein. AtVPS13A has an additional predicted PH domain in the repeating coiled region and AtVPS13B harbors a C2 domain just before the VAB domain while AtVPS13C lacks the C-terminal PH domain (Table 6). The conservation of the domains involved in VPS13 protein targeting in yeast and mamals suggest that plant VPS13 proteins are also associated to multiple cell compatments, including MCSs. In addition, the presence of slight differences in domain organization and the presence of additional domains, like C2 or VPS62-like domains, preclude a higher complexity in the pattern of VPS13 protein localization and their regulation in plant cells. Interestingly, AtVPS13A/At4g17140 was identified in the mitochondrial OM proteome of Arabidopsis thaliana [START_REF] Duncan | Multiple Lines of Evidence Localize Signaling, Morphology, and Lipid Biosynthesis Machinery to the Mitochondrial Outer Membrane of Arabidopsis[END_REF]. Even though the GFP fusions of the 200 N-terminal and C-terminal amino acid residues failed to give a consistent localization, this study gives a first hint for the potential mitochondrial localization of AtVPS13A. AtVPS13A was also found in the A. thaliana mitochondrial complexome and migrated at a molecular weight of 650 kDa on BN-PAGE [START_REF] Senkler | The mitochondrial complexome of Arabidopsis thaliana[END_REF]. An FFAT motif localized in the N-terminal region of AtVPS13A was also identified, suggesting an association with the ER membrane [START_REF] Slee | Systematic Prediction of FFAT Motifs Across Eukaryote Proteomes Identifies Nucleolar and Eisosome Proteins With the Predicted Capacity to Form Bridges to the Endoplasmic Reticulum[END_REF]. In light of these preliminary results, AtVPS13A-C seem to be good candidates as novel VPS13-family LTPs in plants and require further investigation. At3g19190 corresponds to a plant ATG2, also known as PEUP1. Its domain organization and its cellular functions are similar to yeast and mammalian ATG2 proteins [START_REF] Chen | Autophagy in Plant Abiotic Stress Management[END_REF][START_REF] Ding | Plant autophagy : New flavors on the menu[END_REF].

(Insert Table 6 here)

The Sec14-superfamily

The Sec14 domain is widely conserved in Eukaryotes and the Sec14-superfamily is expanded in higher Eukaryotes where more than 20 members can be found in mammals and plants whereas yeast contains only six Sec14 proteins [START_REF] Bankaitis | The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling[END_REF]. In lower Eukaryotes, proteins of this family usually contain only one Sec14 domain whereas in higher Eukaryotes, the Sec14 domain is mainly associated to other domains including the GOLD (Golgi dynamics) domain, the PRELI domain or the plant-specific nodulin domain [START_REF] Bankaitis | The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling[END_REF]. Because of their high number and huge diversity in domain organization, the Sec14 proteins are involved in a wide range of cellular processes including membrane trafficking, lipid metabolism and signaling pathways by regulating PIPs levels and the activity of different GTPases [START_REF] Bankaitis | The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling[END_REF]. Sec14 domains fold in an approximatively 280 aa globular structure with two lobes, formed by an assembly of α-helices and one β-sheet (for a review, see [START_REF] Bankaitis | The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling[END_REF]). The lipid-binding pocket is composed of a βsheet defining the pocket floor and of α-helices forming the wall, the number of β-strands and the orientation and number of α-helices varying among the Sec14 proteins. A helical flexible gate regulates the entry of the cavity with an "open" conformation in absence of lipids and a "closed" conformation when a lipid molecule is inserted in the binding pocket [START_REF] Bankaitis | The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling[END_REF]. Sec14 proteins are able to bind and transport PI, as well as a second ligand that can be diverse hydrophobic compounds like PC, PS, PE, sterols, squalene or α-tocopherol [START_REF] Li | Identification of a Novel Family of Nonclassic Yeast Phosphatidylinositol Transfer Proteins Whose Function Modulates Phospholipase D Activity and Sec14p-independent Cell Growth[END_REF][START_REF] Schaaf | Functional anatomy of phospholipid binding and regulation of phosphoinositide homeostasis by proteins of the sec14 superfamily[END_REF][START_REF] Tripathi | Functional diversification of the chemical landscapes of yeast Sec14-like phosphatidylinositol transfer protein lipid-binding cavities[END_REF]. The role and mechanisms of action of Sec14 PIPTs have been mostly studied in yeast where they are involved in PIPs metabolism and signaling, vesicular trafficking, lipid droplet biogenesis or PS synthesis [START_REF] Lipp | Lipid Exchangers : Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism[END_REF][START_REF] Ren | A phosphatidylinositol transfer protein integrates phosphoinositide signaling with lipid droplet metabolism to regulate a developmental program of nutrient stress-induced membrane biogenesis[END_REF][START_REF] Schaaf | Functional anatomy of phospholipid binding and regulation of phosphoinositide homeostasis by proteins of the sec14 superfamily[END_REF]). It appears that Sec14 proteins are likely involved in regulatory processes rather than in interorganellar bulk lipid transport. The most studied protein is yeast Sec14, that regulates PIPs metabolism and vesicular trafficking at the trans-Golgi network (TGN) (for reviews, see [START_REF] Bankaitis | The Sec14 superfamily and mechanisms for crosstalk between lipid metabolism and lipid signaling[END_REF][START_REF] Grabon | Phosphatidylinositol transfer proteins and instructive regulation of lipid kinase biology[END_REF][START_REF] Lipp | Lipid Exchangers : Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism[END_REF]. Sec14 binds and transports PC and PI in an ATP-independent manner and regulates PI(4)P level in the Golgi by transporting PI in this organelle and promoting its phosphorylation by the PI(4) kinase Pik1 [START_REF] Bankaitis | An essential role for a phospholipid transfer protein in yeast Golgi function[END_REF][START_REF] Lipp | Lipid Exchangers : Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism[END_REF]. The delivery of PI to the Golgi is coupled to the exchange with one PC molecule [START_REF] Schaaf | Functional anatomy of phospholipid binding and regulation of phosphoinositide homeostasis by proteins of the sec14 superfamily[END_REF]. From structural analyses of PC-or PI-bound Sec14 and Sfh1, the closest Sec14 homolog in yeast, it was possible to establish PC-and PI-binding barcodes, corresponding to aa residues establishing specific interactions with PI or PC polar head [START_REF] Lipp | Lipid Exchangers : Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism[END_REF][START_REF] Schaaf | Functional anatomy of phospholipid binding and regulation of phosphoinositide homeostasis by proteins of the sec14 superfamily[END_REF]. The main role of Sec14 is not to transport PI per se, but to render PI accessible to Pik1 for phosphorylation which otherwise happens with very low efficiency when PI is buried in a lipid bilayer [START_REF] Lipp | Lipid Exchangers : Cellular Functions and Mechanistic Links With Phosphoinositide Metabolism[END_REF][START_REF] Schaaf | Functional anatomy of phospholipid binding and regulation of phosphoinositide homeostasis by proteins of the sec14 superfamily[END_REF]. This mechanism is called the "presentation model" in the literature (Kf de Campos & Schaaf, 2017; Lipp et al., 2020). It has to be noticed that efficient PI presentation to Pik1 requires PC binding, explaining why PC transfer activity is required for regulation of PIPs signaling by Sec14 and why PC metabolism is coupled to this signaling pathway [START_REF] Grabon | Phosphatidylinositol transfer proteins and instructive regulation of lipid kinase biology[END_REF][START_REF] Kf De Campos | The regulation of cell polarity by lipid transfer proteins of the SEC14 family[END_REF][START_REF] Schaaf | Functional anatomy of phospholipid binding and regulation of phosphoinositide homeostasis by proteins of the sec14 superfamily[END_REF]. A. thaliana and rice genomes encode for 32 and 27 Sec14 domain-containing proteins respectively (Table 7) (Huang, Ghosh, & Bankaitis, 2016). They are classified into three different families depending on domain organization and sequence similarities.

(Insert Table 7 here)

The Sec14-nodulin family

Fourteen proteins (AtSfh1-14) in A. thaliana present a Sec14 domain fused to a nodulin domain only found in plants (Huang, Ghosh, & Bankaitis, 2016;[START_REF] Montag | Phylogenetic analysis of plant multi-domain SEC14-like phosphatidylinositol transfer proteins and structure-function properties of PATELLIN2[END_REF][START_REF] Vincent | A Sec14p-nodulin domain phosphatidylinositol transfer protein polarizes membrane growth of Arabidopsis thaliana root hairs[END_REF]. The Sec14-nodulin organization is found in angiosperms and some gymnosperms but is absent from more primitive plants such as moss and fern (Huang, Ghosh, & Bankaitis, 2016;Huang et al., 2016;[START_REF] Montag | Phylogenetic analysis of plant multi-domain SEC14-like phosphatidylinositol transfer proteins and structure-function properties of PATELLIN2[END_REF]. Most of these proteins are highly expressed in tissues where extensive polarized membrane growth is required, such as in pollens or roots [START_REF] Ghosh | Sec14-nodulin proteins and the patterning of phosphoinositide landmarks for developmental control of membrane morphogenesis[END_REF][START_REF] Vincent | A Sec14p-nodulin domain phosphatidylinositol transfer protein polarizes membrane growth of Arabidopsis thaliana root hairs[END_REF]. It is predicted to adopt a α-helical coiled-coil structure composed of three antiparallel αhelices [START_REF] Ghosh | Sec14-nodulin proteins and the patterning of phosphoinositide landmarks for developmental control of membrane morphogenesis[END_REF]. 3D modeling of AtSfh1 Sec14 domain shows a similar fold as for the yeast Sec14 protein and highlights a conservation of the yeast PI-and PC-binding barcodes among the Sec14-nodulin proteins (Huang et al., 2016). The ability of AtSfh1 and other Sec14-nodulin proteins to transport both PI and PC was confirmed by complementation of the yeast sec14 mutant combined with in vitro transfer assays [START_REF] Böhme | The Arabidopsis COW1 gene encodes a phosphatidylinositol transfer protein essential for root hair tip growth[END_REF]Huang et al., 2016;[START_REF] Vincent | A Sec14p-nodulin domain phosphatidylinositol transfer protein polarizes membrane growth of Arabidopsis thaliana root hairs[END_REF]. These results suggest that this family might also regulate PIPs signaling by stimulating PIPs kinase activity. The occurrence of this mechanism for plant Sec14-nodulin proteins was further supported by functional analysis of AtSfh1, a protein mainly expressed during and involved in root hair elongation [START_REF] Böhme | The Arabidopsis COW1 gene encodes a phosphatidylinositol transfer protein essential for root hair tip growth[END_REF][START_REF] Vincent | A Sec14p-nodulin domain phosphatidylinositol transfer protein polarizes membrane growth of Arabidopsis thaliana root hairs[END_REF]. During root hair elongation, a huge polarized transport of vesicles to the root tip elongation zone is required and involves the maintenance of a concentration gradient of PI(4,5)P 2 in the PM along the elongating root hair. AtSfh1 associates specifically to PI(4,5)P 2 in PM via a polybasic stretch located at the C-terminal of the nodulin domain [START_REF] Ghosh | Sec14-nodulin proteins and the patterning of phosphoinositide landmarks for developmental control of membrane morphogenesis[END_REF][START_REF] Vincent | A Sec14p-nodulin domain phosphatidylinositol transfer protein polarizes membrane growth of Arabidopsis thaliana root hairs[END_REF]. The binding of AtSfh1 to PM and its oligomerization via the nodulin domain were suggested to promote the formation of microdomains enriched in PI(4,5)P 2 and to maintain the PI(4,5)P 2 gradient [START_REF] Ghosh | Sec14-nodulin proteins and the patterning of phosphoinositide landmarks for developmental control of membrane morphogenesis[END_REF]Huang, Ghosh, & Bankaitis, 2016). In addition, AtSfh1 might also regulate the level of PI(4,5)P 2 by stimulating PI(4) kinase activity and PI(4)P synthesis, which can be subsequently used as a substrate for PI(4,5)P 2 synthesis. Because the Sec14 domain of several Sec14-nodulin proteins are able to complement yeast phenotype and to transport both PI and PC, it is likely that the regulation of PIPs metabolism by the presentation model is a general mechanism of action of Sec14-nodulin proteins (Huang, et al., 2016;[START_REF] Kf De Campos | The regulation of cell polarity by lipid transfer proteins of the SEC14 family[END_REF].

The Patellin family

Patellins are characterized by the association of the Sec14 domain to a GOLD domain and are present in plants as well as in metazoans. In plants, Patellins are found in angiosperms and gymnosperms and A. thaliana genome encodes six Patellin genes (AtPATL1-6) (Table 7) [START_REF] Peterman | Molecular cloning and characterization of patellin1, a novel sec14-related protein, from zucchini (Cucurbita pepo)[END_REF][START_REF] Zhou | Patellin protein family functions in plant development and stress response[END_REF]. Patellins have a variable N-terminal extension differing in both length and aa composition [START_REF] Peterman | Patellin1, a novel Sec14-like protein, localizes to the cell plate and binds phosphoinositides[END_REF][START_REF] Peterman | Molecular cloning and characterization of patellin1, a novel sec14-related protein, from zucchini (Cucurbita pepo)[END_REF]. They are expressed in many tissues during plant development, in particular in cells with high mitotic activity, and are responsive to biotic and abiotic stress [START_REF] Hua-Ying | Genome-wide identification, phylogeny, and expression analysis of Sec14-like PITP gene family in sugarcane[END_REF][START_REF] Peterman | Patellin1, a novel Sec14-like protein, localizes to the cell plate and binds phosphoinositides[END_REF][START_REF] Tejos | PATELLINS are regulators of auxin-mediated PIN1 relocation and plant development in Arabidopsis thaliana[END_REF]. Patellins do not contain TM domains and are found to be cytosolic and associated to membranes, in particular to PM [START_REF] Peterman | Patellin1, a novel Sec14-like protein, localizes to the cell plate and binds phosphoinositides[END_REF][START_REF] Suzuki | Identification of Phosphoinositide-Binding Protein PATELLIN2 as a Substrate of Arabidopsis MPK4 MAP Kinase during Septum Formation in Cytokinesis[END_REF][START_REF] Tejos | PATELLINS are regulators of auxin-mediated PIN1 relocation and plant development in Arabidopsis thaliana[END_REF][START_REF] Wu | Arabidopsis EXO70A1 recruits Patellin3 to the cell membrane independent of its role as an exocyst subunit : A subunit-specific role of EXO70A1[END_REF]. In dividing cells, AtPATLs are also localized to the cell plate, suggesting a role during cytokinesis [START_REF] Peterman | Patellin1, a novel Sec14-like protein, localizes to the cell plate and binds phosphoinositides[END_REF][START_REF] Tejos | PATELLINS are regulators of auxin-mediated PIN1 relocation and plant development in Arabidopsis thaliana[END_REF]. The PI-binding barcode, but not the PC-binding barcode, is conserved among the A. thaliana Patellins, suggesting they can transport PI and probably other yet unidentified substrates other than PC (Huang, et al., 2016;[START_REF] Peterman | Patellin1, a novel Sec14-like protein, localizes to the cell plate and binds phosphoinositides[END_REF]. All Patellins studied until now are able to bind several PIPs in vitro [START_REF] Montag | Phylogenetic analysis of plant multi-domain SEC14-like phosphatidylinositol transfer proteins and structure-function properties of PATELLIN2[END_REF][START_REF] Peterman | Patellin1, a novel Sec14-like protein, localizes to the cell plate and binds phosphoinositides[END_REF][START_REF] Suzuki | Identification of Phosphoinositide-Binding Protein PATELLIN2 as a Substrate of Arabidopsis MPK4 MAP Kinase during Septum Formation in Cytokinesis[END_REF]. However, the association of AtPATL2 and AtPATL3 with the PM is mediated by protein-protein interactions via the GOLD domain and not by PIPs binding [START_REF] Suzuki | Identification of Phosphoinositide-Binding Protein PATELLIN2 as a Substrate of Arabidopsis MPK4 MAP Kinase during Septum Formation in Cytokinesis[END_REF][START_REF] Wu | Arabidopsis EXO70A1 recruits Patellin3 to the cell membrane independent of its role as an exocyst subunit : A subunit-specific role of EXO70A1[END_REF]. Information concerning the roles of Patellins during plant development and in response to stress is scarce. AtPATL1 is involved in cold and salt stress resistance [START_REF] Chu | AtCaM4 interacts with a Sec14like protein, PATL1, to regulate freezing tolerance in Arabidopsis in a CBF-independent manner[END_REF][START_REF] Zhou | Patellin1 Negatively Modulates Salt Tolerance by Regulating PM Na+/H+ Antiport Activity and Cellular Redox Homeostasis in Arabidopsis[END_REF] whereas AtPATL3 and 6 are involved in plant resistance to Alfalfa mosaic virus (AMV) by interacting with the AMV movement protein, impairing viral particle targeting to PDs and cell-to-cell movement [START_REF] Peiro | Patellins 3 and 6, two members of the Plant Patellin family, interact with the movement protein of Alfalfa mosaic virus and interfere with viral movement[END_REF]. A role in membrane trafficking during cytokinesis, salt stress response, vacuole biogenesis and autophagy is also suspected. AtPATLs are recruited to cell plate during cytokinesis, but their role in the formation or maturation of such structure is unknown [START_REF] Peterman | Patellin1, a novel Sec14-like protein, localizes to the cell plate and binds phosphoinositides[END_REF][START_REF] Tejos | PATELLINS are regulators of auxin-mediated PIN1 relocation and plant development in Arabidopsis thaliana[END_REF]. AtPATL1 is overexpressed in response to high salts and interacts with the PM Na + transporter SOS1, reducing Na + transport and likely promoting salt stress tolerance [START_REF] Zhou | Patellin1 Negatively Modulates Salt Tolerance by Regulating PM Na+/H+ Antiport Activity and Cellular Redox Homeostasis in Arabidopsis[END_REF]. Finally, AtPATL1 and 2 interact with AMSH3, a deubiquitinase enzyme involved in vesicular trafficking, vacuole biogenesis and autophogosome degradation [START_REF] Isono | The Deubiquitinating Enzyme AMSH3 Is Required for Intracellular Trafficking and Vacuole Biogenesis in Arabidopsis thaliana[END_REF][START_REF] Katsiarimpa | The Deubiquitinating Enzyme AMSH1 and the ESCRT-III Subunit VPS2.1 Are Required for Autophagic Degradation in Arabidopsis[END_REF]. Because of their ability to bind a wide range of PIPs, roles in cell signaling rather than bulk lipid transport are suspected [START_REF] Zhou | Patellin protein family functions in plant development and stress response[END_REF]. Unfortunately, the molecular mechanisms involved in the regulation of Patellin function and whether their putative lipid transfer activity is required to sustain this function is still unknown.

Stand-alone Sec14

A. thaliana contains twelve stand-alone Sec14 proteins that can be divided into five clades that might define different biochemical properties and biological functions (Table 7) (Huang, Ghosh, & Bankaitis, 2016). A few proteins of this huge family were characterized and they seem to play a role in chloroplast development as well as in biotic and abiotic stress response [START_REF] Hertle | A Sec14 domain protein is required for photoautotrophic growth and chloroplast vesicle formation in Arabidopsis thaliana[END_REF][START_REF] Kearns | Novel developmentally regulated phosphoinositide binding proteins from soybean whose expression bypasses the requirement for an essential phosphatidylinositol transfer protein in yeast[END_REF][START_REF] Kiba | SEC14 phospholipid transfer protein is involved in lipid signaling-mediated plant immune responses in Nicotiana benthamiana[END_REF]. Most of these proteins in plants were first identified by their ability to complement the yeast sec14 mutant. This includes AtPITP11 [START_REF] Jouannic | Isolation of a cDNA from Arabidopsis thaliana that complements the sec14 mutant of yeast[END_REF], soybean Ssh1 and Ssh2 [START_REF] Kearns | Novel developmentally regulated phosphoinositide binding proteins from soybean whose expression bypasses the requirement for an essential phosphatidylinositol transfer protein in yeast[END_REF] and N. benthamiana NbSec14 [START_REF] Kiba | A novel Sec14 phospholipid transfer protein from Nicotiana benthamiana is up-regulated in response to Ralstonia solanacearum infection, pathogen associated molecular patterns and effector molecules and involved in plant immunity[END_REF]. AtPITP11 is mainly expressed in leaves and flowers and transport PI in vitro [START_REF] Jouannic | Isolation of a cDNA from Arabidopsis thaliana that complements the sec14 mutant of yeast[END_REF], but no further information about its subcellular localization and function are available. Soybean Ssh1 is mainly expressed in leaves and roots whereas Ssh2 shows the highest expression level in developing seeds [START_REF] Kearns | Novel developmentally regulated phosphoinositide binding proteins from soybean whose expression bypasses the requirement for an essential phosphatidylinositol transfer protein in yeast[END_REF]. Both proteins are membrane associated but only Ssh2 is able to transport PI, but not PC, in vitro, whereas Ssh1 was not able transport PI and PC in the tested condition, suggesting it has no lipid transport activity or transports other unidentified molecules [START_REF] Kearns | Novel developmentally regulated phosphoinositide binding proteins from soybean whose expression bypasses the requirement for an essential phosphatidylinositol transfer protein in yeast[END_REF]. Both proteins bind PI(4,5)P 2 and Ssh1 also associates to PI(3,5)P 2 in vitro whereas Ssh2 seems to associate to PS and PA [START_REF] Kearns | Novel developmentally regulated phosphoinositide binding proteins from soybean whose expression bypasses the requirement for an essential phosphatidylinositol transfer protein in yeast[END_REF]. In response to hyperosmotic stress, a rapid increase of Ssh1 phosphorylation mediated by the salt-induced SPK1 and SPK2 kinases was observed, decreasing Ssh1 affinity for membranes [START_REF] Monks | Hyperosmotic stress induces the rapid phosphorylation of a soybean phosphatidylinositol transfer protein homolog through activation of the protein kinases SPK1 and SPK2[END_REF]. As Ssh1 increases in vitro PI(3) kinase and PI(4) kinase activities, it was proposed that Ssh1 regulates PIPs signaling in response to osmotic stress in soybean via modulation of PI kinases activity [START_REF] Monks | Hyperosmotic stress induces the rapid phosphorylation of a soybean phosphatidylinositol transfer protein homolog through activation of the protein kinases SPK1 and SPK2[END_REF]. NbSec14, a stand-alone Sec14 protein able to transfer PI and PC in vitro, is involved in lipid signaling during plant immune response to the bacteria Ralstonia solanacearum [START_REF] Kiba | A novel Sec14 phospholipid transfer protein from Nicotiana benthamiana is up-regulated in response to Ralstonia solanacearum infection, pathogen associated molecular patterns and effector molecules and involved in plant immunity[END_REF][START_REF] Kiba | SEC14 phospholipid transfer protein is involved in lipid signaling-mediated plant immune responses in Nicotiana benthamiana[END_REF]. NbSec14 is upregulated during infection and NbSec14 siRNA plants show a higher susceptibility to R. solanacearum. In these lines, no increase in PA and DAG levels, two key lipids involved in plant immune response signaling, was observed upon infection, in accordance with a decreased DAG kinase, phospholipase D and phospholipase C activities in total plant extracts [START_REF] Kiba | SEC14 phospholipid transfer protein is involved in lipid signaling-mediated plant immune responses in Nicotiana benthamiana[END_REF]. More recently, the first identified chloroplastic Sec14 protein, AtPITP7 (also called CPSFL1), was shown to be involved in chloroplast development and photoautotropic growth [START_REF] Hertle | A Sec14 domain protein is required for photoautotrophic growth and chloroplast vesicle formation in Arabidopsis thaliana[END_REF]. AtPITP7 accumulates in plastid stroma vesicles and is involved in vesicular trafficking required for thylakoid biogenesis. In vitro, AtPITP7 binds PA, SQDG and PIPs but is only able to extract and transfer PI(4)P between liposomes [START_REF] Hertle | A Sec14 domain protein is required for photoautotrophic growth and chloroplast vesicle formation in Arabidopsis thaliana[END_REF]. Thus, this protein might regulate lipid signaling between the inner envelope of plastids and thylakoids.

nsLTPs

The non-specific LTP (nsLTP) is a land plant-specific class of LTPs that can bind a wide variety of substrates in vitro. They are encoded by large gene families, with 79 and 77 members in A. thaliana and rice respectively [START_REF] Salminen | Lipid transfer proteins : Classification, nomenclature, structure, and function[END_REF]. NsLTPs are small basic proteins (7 to 10KDa) characterized by the presence of eight conserved Cys residues. They fold into a compact globular structure composed of four α-helices with a C-terminal unstructured tail (for detailed reviews, see [START_REF] Carvalho | Role of plant lipid transfer proteins in plant cell physiology-a concise review[END_REF][START_REF] Salminen | Lipid transfer proteins : Classification, nomenclature, structure, and function[END_REF]). NsLTPs possess an N-terminal peptide sequence that targets proteins to the secretory pathway, most of them being then secreted in the apoplast space. They are soluble but some of them can bind membranes and liposomes in vitro while others can be post-translationally associated to a glycosylphosphatidylinositol (GPI) anchor. NsLTPs are able to bind a wide variety of substrates, like phospholipids, galactoglycerolipids, free FAs, acyl-CoA, lysolipids or prostaglandin [START_REF] Kader | LIPID-TRANSFER PROTEINS IN PLANTS[END_REF][START_REF] Salminen | Lipid transfer proteins : Classification, nomenclature, structure, and function[END_REF]. Proteins from this family are mainly involved in 1) cell wall synthesis, 2) pollen and seed development, 3) embryogenesis, 4) defense again pathogens, 5) long-distance signaling and 6) stress response [START_REF] Carvalho | Role of plant lipid transfer proteins in plant cell physiology-a concise review[END_REF][START_REF] Edqvist | Plant lipid transfer proteins : Are we finally closing in on the roles of these enigmatic proteins[END_REF][START_REF] Kader | LIPID-TRANSFER PROTEINS IN PLANTS[END_REF][START_REF] Salminen | Lipid transfer proteins : Classification, nomenclature, structure, and function[END_REF]. Most of nsLTPs are likely not involved in the intracellular transfer of lipids dedicated to membrane biogenesis. However, such a role might be supported by two nsLTPs, AsE246 and MtN5, in legumes during nodulation in response to nitrogen starvation and by one nsLTP, GhLTPG1, involved in cotton fiber elongation [START_REF] Deng | GhLTPG1, a cotton GPI-anchored lipid transfer protein, regulates the transport of phosphatidylinositol monophosphates and cotton fiber elongation[END_REF][START_REF] Lei | A Nodule-Specific Lipid Transfer Protein AsE246 Participates in Transport of Plant-Synthesized Lipids to Symbiosome Membrane and Is Essential for Nodule Organogenesis in Chinese Milk Vetch[END_REF][START_REF] Pii | The Medicago truncatula N5 Gene Encoding a Root-Specific Lipid Transfer Protein Is Required for the Symbiotic Interaction with Sinorhizobium meliloti[END_REF].

During nitrogen starvation, legume roots are able to establish symbiotic relationships with rhizobial bacteria or arbuscular mycorrhizal fungi that will provide nitrogen to the plant in exchange of carbon [START_REF] Downie | Legume nodulation[END_REF][START_REF] Udvardi | Transport and Metabolism in Legume-Rhizobia Symbioses[END_REF][START_REF] Verma | Biogenesis of the peribacteriod membrane in root nodules[END_REF]. This symbiotic process occurs in special structures formed in roots of infected plants called nodules where bacteria are enclosed in a special cell compartment, the symbiosome, in which they will divide and differentiate into nitrogenfixing bacteroids. Symbiosome membrane lipids arise from the host plant cell and a tremendous amount of lipid synthesis and transfer is required for nodule formation [START_REF] Harrison | Exocytosis for endosymbiosis : Membrane trafficking pathways for development of symbiotic membrane compartments[END_REF][START_REF] Verma | Biogenesis of the peribacteriod membrane in root nodules[END_REF]. Symbiosome membranes formation relies on Golgi-derived vesicle trafficking [START_REF] Harrison | Exocytosis for endosymbiosis : Membrane trafficking pathways for development of symbiotic membrane compartments[END_REF]. They are composed of phospholipids (PC, PE, PI and PG) and DGDG [START_REF] Gaude | The Galactolipid Digalactosyldiacylglycerol Accumulates in the Peribacteroid Membrane of Nitrogen-fixing Nodules of Soybean and Lotus[END_REF][START_REF] Lei | A Nodule-Specific Lipid Transfer Protein AsE246 Participates in Transport of Plant-Synthesized Lipids to Symbiosome Membrane and Is Essential for Nodule Organogenesis in Chinese Milk Vetch[END_REF], suggesting that chloroplast and likely non-vesicular lipid trafficking might be involved in the biogenesis of these membranes. In line with this, AsE246, a nsLTP specifically expressed during nodulation and located to the symbiosome membrane, is required for nodule formation and symbiosomes development in Astragalus sinicus infected by the rhizobacteria Mesorhizobium huakuii [START_REF] Chou | Thirteen nodule-specific or nodule-enhanced genes encoding products homologous to cysteine cluster proteins or plant lipid transfer proteins are identified in Astragalus sinicus L. by suppressive subtractive hybridization[END_REF][START_REF] Lei | A Nodule-Specific Lipid Transfer Protein AsE246 Participates in Transport of Plant-Synthesized Lipids to Symbiosome Membrane and Is Essential for Nodule Organogenesis in Chinese Milk Vetch[END_REF]. AsE246 is able to bind different phospholipids and galactoglycerolipids [START_REF] Lei | A Nodule-Specific Lipid Transfer Protein AsE246 Participates in Transport of Plant-Synthesized Lipids to Symbiosome Membrane and Is Essential for Nodule Organogenesis in Chinese Milk Vetch[END_REF]. However, whether AsE246 promotes lipid transport from cell organelles to symbiosome membranes remains to be defined. Another Medicago truncatula nsLTP, MtN5, plays a role in the regulation of root nodulation during Sinorhizobium meliloti symbiosis [START_REF] Pii | The Medicago truncatula N5 Gene Encoding a Root-Specific Lipid Transfer Protein Is Required for the Symbiotic Interaction with Sinorhizobium meliloti[END_REF][START_REF] Pii | The non-specific lipid transfer protein N5 of Medicago truncatula is implicated in epidermal stages of rhizobium-host interaction[END_REF][START_REF] Pii | The involvement of Medicago truncatula non-specific lipid transfer protein N5 in the control of rhizobial infection[END_REF]. MtN5 is expressed early during nodule formation and is required for optimal bacterial infection and nodule invasion. In vitro, MtN5 binds to some lyso-PC species [START_REF] Pii | The Medicago truncatula N5 Gene Encoding a Root-Specific Lipid Transfer Protein Is Required for the Symbiotic Interaction with Sinorhizobium meliloti[END_REF]. Lipidomic analyses of roots overexpressing MtN5 highlighted a global increase in lipid content, in particular of DGDG, MGDG, PE and glucosyl-ceramide. This increase is concomitant with the modification of the expression of genes involved in lipid metabolism and lipid transport [START_REF] Santi | Genome-Wide Transcriptional Changes and Lipid Profile Modifications Induced by Medicago truncatula N5 Overexpression at an Early Stage of the Symbiotic Interaction with Sinorhizobium meliloti[END_REF]. These results suggest that MtN5 might regulate lipid synthesis and/or transport during nodulation. Another role in the regulation of nodulation by lipid signalization has been proposed as 1) MtN5 is able to bind lyso-PC in vitro [START_REF] Pii | The Medicago truncatula N5 Gene Encoding a Root-Specific Lipid Transfer Protein Is Required for the Symbiotic Interaction with Sinorhizobium meliloti[END_REF], a lipid signal involved in arbuscular mycorrhizal symbiosis [START_REF] Drissner | Lyso-Phosphatidylcholine Is a Signal in the Arbuscular Mycorrhizal Symbiosis[END_REF], and 2) overexpression of MtN5 triggers deregulation of the expression of genes involved in the synthesis of lipid signaling molecules such as PIPs kinases, phospholipases C or Sec14-like proteins [START_REF] Santi | Genome-Wide Transcriptional Changes and Lipid Profile Modifications Induced by Medicago truncatula N5 Overexpression at an Early Stage of the Symbiotic Interaction with Sinorhizobium meliloti[END_REF]. All these data suggest that non-vesicular lipid transport could also be involved in membrane biogenesis during plant-microorganism symbiosis in response to nitrogen starvation. This might be particularly true for DGDG, as this plastidial lipid has never been shown to be transported via vesicular routes.

Cotton fiber synthesis starts from ovule epidermal cells and is divided in four steps: 1) fiber initiation, 2) cell elongation, 3) secondary wall deposition and 4) maturation [START_REF] Kim | Cotton fiber growth in planta and in vitro. Models for plant cell elongation and cell wall biogenesis[END_REF].

The cell elongation step requires a huge amount of lipids to sustain membrane synthesis in growing cells [START_REF] Wanjie | Identification and quantification of glycerolipids in cotton fibers : Reconciliation with metabolic pathway predictions from DNA databases[END_REF]. The GPI-anchored nsLTP GhLTPG1 is highly expressed in elongating fibers and is able to specifically bind and transport PI-monophosphates [START_REF] Deng | GhLTPG1, a cotton GPI-anchored lipid transfer protein, regulates the transport of phosphatidylinositol monophosphates and cotton fiber elongation[END_REF]. GhLTPG1 harbors a peptide signal and a GPI anchor, both required for its localization to the PM [START_REF] Deng | GhLTPG1, a cotton GPI-anchored lipid transfer protein, regulates the transport of phosphatidylinositol monophosphates and cotton fiber elongation[END_REF]. Silencing of GhLTPG1 slightly reduces cotton fiber length and the expression of cotton-fiber elongation genes. A small decrease in polar lipids, in particular of PI, was also observed [START_REF] Deng | GhLTPG1, a cotton GPI-anchored lipid transfer protein, regulates the transport of phosphatidylinositol monophosphates and cotton fiber elongation[END_REF], suggesting that GhLTPG1 might be involved in lipid transport to sustain fiber elongation.

3 Lipid transport mediated by other proteins 3.1 NDPK-D Nucleoside diphosphate kinases (NDPKs) are a family of proteins conserved throughout evolution with a primary role in the exchange of γ-phosphate between nucleosides-tri-phosphate and nucleoside-di-phosphate [START_REF] Boissan | The NDPK/NME superfamily : State of the art[END_REF]. They act as symmetrical homo-hexamers and are present in different cell compartments where they can play a role in many cellular processes [START_REF] Boissan | The NDPK/NME superfamily : State of the art[END_REF][START_REF] Janin | Threedimensional structure of nucleoside diphosphate kinase[END_REF]. Interestingly, one well studied homolog in mammals, NDPK-D, is located in mitochondria IMS and is known to bind membranes and transfer CL [START_REF] Epand | Novel lipid transfer property of two mitochondrial proteins that bridge the inner and outer membranes[END_REF][START_REF] Schlattner | Dual Function of Mitochondrial Nm23-H4 Protein in Phosphotransfer and Intermembrane Lipid Transfer[END_REF][START_REF] Tokarska-Schlattner | The nucleoside diphosphate kinase D (NM23-H4) binds the inner mitochondrial membrane with high affinity to cardiolipin and couples nucleotide transfer with respiration[END_REF]. NDPK-D membrane binding is mediated by a cationic motif R89-R90-K91 located at the surface of the hexamer, which associates with negatively charged lipids, in particular CL [START_REF] Tokarska-Schlattner | The nucleoside diphosphate kinase D (NM23-H4) binds the inner mitochondrial membrane with high affinity to cardiolipin and couples nucleotide transfer with respiration[END_REF]. The R90 residue, specific to the mitochondrial NDPK-D ortholog in humans, is essential for CL and membrane binding (Tokarska- [START_REF] Tokarska-Schlattner | The nucleoside diphosphate kinase D (NM23-H4) binds the inner mitochondrial membrane with high affinity to cardiolipin and couples nucleotide transfer with respiration[END_REF]. As one CL binding site is present per monomer, NDPK-D hexamers are able to tether liposomes containing CL in vitro and OM-IM in vivo [START_REF] Epand | Novel lipid transfer property of two mitochondrial proteins that bridge the inner and outer membranes[END_REF][START_REF] Kagan | NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy[END_REF][START_REF] Tokarska-Schlattner | The nucleoside diphosphate kinase D (NM23-H4) binds the inner mitochondrial membrane with high affinity to cardiolipin and couples nucleotide transfer with respiration[END_REF]. Membrane binding inhibits NDPK-D phosphotransferase activity and promotes CL transfer from IM to OM, inducing apoptosis and mitophagy and linking NDPK-D lipid transport function to CL signaling [START_REF] Kagan | NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy[END_REF][START_REF] Schlattner | Dual Function of Mitochondrial Nm23-H4 Protein in Phosphotransfer and Intermembrane Lipid Transfer[END_REF][START_REF] Schlattner | NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy[END_REF].

Two NDPK-D homologs are found in A. thaliana (NDPK3a and NDPK3b), NDPK3b being expressed at a very low level (Table 8) [START_REF] Hammargren | On the phylogeny, expression and targeting of plant nucleoside diphosphate kinases[END_REF]. Both proteins have been detected in mitochondrial proteome [START_REF] Heazlewood | Experimental analysis of the Arabidopsis mitochondrial proteome highlights signaling and regulatory components, provides assessment of targeting prediction programs, and indicates plant-specific mitochondrial proteins[END_REF]) and NDPK3a-GFP fusion was found to be located in mitochondria [START_REF] Carrie | Approaches to defining dual-targeted proteins in Arabidopsis[END_REF] or in mitochondria and plastids [START_REF] Hammargren | On the phylogeny, expression and targeting of plant nucleoside diphosphate kinases[END_REF][START_REF] Luzarowski | Affinity purification with metabolomic and proteomic analysis unravels diverse roles of nucleoside diphosphate kinases[END_REF]. Interestingly, NDPK3a was also found in proteomic analysis of the MTL complex, a mitochondrial complex involved in lipid transport (see below) [START_REF] Michaud | AtMic60 Is Involved in Plant Mitochondria Lipid Trafficking and Is Part of a Large Complex[END_REF]. However, Western blot analysis suggests that this protein probably co-migrates with the MTL complex on native gel rather than being a real MTL complex component. In addition, the R90 residue required for membrane binding of human NDPK-D is not conserved in A. thaliana, suggesting that NDPK3 could not bind membrane lipids (Figure 4). However, in pea, NDPK3 is strongly associated with the intermembrane space (IMS) leaflet of the IM and interacts with the ANT carrier [START_REF] Knorpp | Plant mitochondrial nucleoside diphosphate kinase is attached to the membrane through interaction with the adenine nucleotide translocator[END_REF], suggesting that membrane binding could be mediated by protein-protein interactions in plants (Figure 3C(i)). Further analyses are required to understand if NDPK3a is a component of the MTL complex and if it transports CL between mitochondrial OM and IM.

Enzymes involved in lipid metabolism

In yeast and mammals, several enzymes involved in lipid synthesis are enriched at MCSs, in particular at ER-mitochondria MCSs and at ER-PM MCSs [START_REF] Gaigg | Characterization of a microsomal subfraction associated with mitochondria of the yeast, Saccharomyces cerevisiae. Involvement in synthesis and import of phospholipids into mitochondria[END_REF][START_REF] Pichler | A subfraction of the yeast endoplasmic reticulum associates with the plasma membrane and has a high capacity to synthesize lipids[END_REF][START_REF] Vance | Phospholipid synthesis in a membrane fraction associated with mitochondria[END_REF]. In plants, enzymes involved in lipid metabolism have also been detected in ER-PM and in ER-plastids MCSs [START_REF] Andersson | Optical manipulation reveals strong attracting forces at membrane contact sites between endoplasmic reticulum and chloroplasts[END_REF][START_REF] Larsson | LysoPC acyltransferase/PC transacylase activities in plant plasma membrane and plasma membrane-associated endoplasmic reticulum[END_REF]. In addition, during Pi starvation, the phospholipase D PLDζ2 is enriched at vacuole-mitochondria and vacuole-chloroplasts MCSs, whereas an even distribution along the vacuole membrane is observed when A. thaliana plants are grown in Pi-sufficient conditions [START_REF] Yamaryo | Phosphate availability affects the tonoplast localization of PLDζ2, an Arabidopsis thaliana phospholipase D[END_REF]. An increasing number of evidences suggests that such localization is important to provide an efficient transport of lipids between membranes. This is the case for instance in yeast for the transport of PS at ER-mitochondria MCSs, where the localization of PS synthase at this junction increases the efficiency of PS transport to mitochondria [START_REF] Kannan | Phosphatidylserine synthesis at membrane contact sites promotes its transport out of the ER[END_REF]. Several hypotheses can explain why the localization of lipid-synthesizing enzymes at MCSs is important for non-vesicular lipid transfer: 1) local synthesis can create microdomains with special lipid composition facilitating lipid extrusion and transfer; 2) the local enrichment of a lipid at MCSs can favor its transport by energy-independent LTPs following its concentration gradient, 3) the modification of a lipid at MCSs can promote the formation of lipid species more competent for nonvesicular transport (i.e. less hydrophobic), and/or 4) the coupling between synthesis and transfer can be important to rapidly regulate organelle biogenesis during cell division or in response to stress. In addition, several examples have demonstrated that enzymes can also work in trans at MCSs, meaning that they can modify a lipid substrate located in the juxtaposed membrane. This is the case of the phosphatidylserine decarboxylase PSD1 in mitochondria IM that can decarboxylate OM PS to produce PE at OM-IM MCSs [START_REF] Aaltonen | MICOS and phospholipid transfer by Ups2-Mdm35 organize membrane lipid synthesis in mitochondria[END_REF]. This mechanism is involved in the regulation of lipid composition at MCSs but is not involved in the lipid transport process per se.

PC remodeling at ER-plastids MCSs

Lyso-PC can be spontaneously transferred between membranes because of its low hydrophobicity. In plants, lyso-PC synthesis at ER-plastids MCSs might be one of the mechanisms involved in the transport of lipid precursors from ER to chloroplast to fulfill galactoglycerolipid synthesis via the Eukaryotic pathway. This idea was supported by pulse chase experiments and by the presence of several enzymes involved in the synthesis of lyso-PC from PC and in its reacylation at ER-chloroplasts MCSs or in chloroplasts OE (Figure 3D(i)) [START_REF] Bessoule | Synthesis of phosphatidylcholine in the chloroplast envelope after import of lysophosphatidylcholine from endoplasmic reticulum membranes[END_REF][START_REF] Jessen | Two activities of long-chain acyl-coenzyme A synthetase are involved in lipid trafficking between the endoplasmic reticulum and the plastid in Arabidopsis[END_REF][START_REF] Mongrand | Import of lyso-phosphatidylcholine into chloroplasts likely at the origin of eukaryotic plastidial lipids[END_REF][START_REF] Tan | A Brassica napus Lipase Locates at the Membrane Contact Sites Involved in Chloroplast Development[END_REF]. In Brassica napus, the lipase BnCLIP1 is located at ERchloroplast MCSs, where it might be involved in lyso-lipid synthesis from ER phospholipids [START_REF] Tan | A Brassica napus Lipase Locates at the Membrane Contact Sites Involved in Chloroplast Development[END_REF]. Andersson et al. show that cytosolic lipases can generate lyso-PC molecules which are subsequently used for galactoglycerolipid synthesis [START_REF] Andersson | The involvement of cytosolic lipases in converting phosphatidyl choline to substrate for galactolipid synthesis in the chloroplast envelope[END_REF]. In A. thaliana, the longchain acyl-CoA synthetases LACS4 and LASC9 are localized in the ER and the chloroplast OE respectively and double lacs4lacs9 mutants show a decrease in the content of galactoglycerolipids arising from the Eukaryotic pathway [START_REF] Jessen | Two activities of long-chain acyl-coenzyme A synthetase are involved in lipid trafficking between the endoplasmic reticulum and the plastid in Arabidopsis[END_REF]. Thus, these LACSs have been proposed to play a role in the creation of a local pool of acyl-CoA at ER-chloroplasts MCSs that might be used by LPCAT to promote PC synthesis in the chloroplast envelope [START_REF] Jessen | Two activities of long-chain acyl-coenzyme A synthetase are involved in lipid trafficking between the endoplasmic reticulum and the plastid in Arabidopsis[END_REF]. In addition, LPCAT activity has been detected in the chloroplast envelope of several plant species [START_REF] Bessoule | Synthesis of phosphatidylcholine in the chloroplast envelope after import of lysophosphatidylcholine from endoplasmic reticulum membranes[END_REF][START_REF] Karki | Metabolically distinct pools of phosphatidylcholine are involved in trafficking of fatty acids out of and into the chloroplast for membrane production[END_REF]. However, the analyses of lpcat1lpcat2 mutants in A. thaliana, the two main enzymes responsible for LPCAT activity, demonstrated that LPCAT activity, and likely lyso-PC transport, is not essential for chloroplastic lipid synthesis via the Eukaryotic pathway [START_REF] Karki | Metabolically distinct pools of phosphatidylcholine are involved in trafficking of fatty acids out of and into the chloroplast for membrane production[END_REF]. Interestingly, pulse chase labelling experiments performed in this work support a model in which the LPCAT1/2 enzymes are involved in the incorporation of newly synthesized chloroplastic FAs into PC by lyso-PC acylation. PC is then translocated back to the ER where it can also be synthesized by the de novo pathway from glycerol-3-phosphate and acyl-CoA, leading to two distinct pools of PC in the ER [START_REF] Karki | Metabolically distinct pools of phosphatidylcholine are involved in trafficking of fatty acids out of and into the chloroplast for membrane production[END_REF]. Thus, this current model suggests that LPCAT1/2 are more likely involved in chloroplast to ER PC transport than in the Eukaryotic pathway of galactoglycerolipid synthesis. Transport of PC via the lyso-PC intermediate could also occur at ER-PM MCSs in plants where LPCAT activity has been detected in pea [START_REF] Larsson | LysoPC acyltransferase/PC transacylase activities in plant plasma membrane and plasma membrane-associated endoplasmic reticulum[END_REF].

DGD1

MGDG synthesis starts by the addition of a galactose residue to a DAG backbone. Bulk MGDG synthesis takes place at the plastid IE and is catalysed by MGD1, while MGD2/3 operate at the plastid OE in non-photosynthetic tissues or during specific stress conditions, typically Pi starvation [START_REF] Awai | Two types of MGDG synthase genes, found widely in both 16:3 and 18:3 plants, differentially mediate galactolipid syntheses in photosynthetic and nonphotosynthetic tissues in Arabidopsis thaliana[END_REF][START_REF] Kobayashi | Type-B monogalactosyldiacylglycerol synthases are involved in phosphate starvation-induced lipid remodeling, and are crucial for low-phosphate adaptation[END_REF]. DGDG synthesis requires the addition of another galactose residue moiety to MGDG, a reaction catalysed by DGD1 and DGD2 at the plastid OE (Figure 3D(ii)) [START_REF] Kelly | Disruption of the Two Digalactosyldiacylglycerol Synthase Genes DGD1 and DGD2 in Arabidopsis Reveals the Existence of an Additional Enzyme of Galactolipid Synthesis[END_REF]. Hence, DGDG synthesis requires the transport of MGDG from the IE to the OE. The Nterminal region of DGD1, NDGD1, has been shown to promote lipid transport between the plastid IE and OE [START_REF] Kelly | Synthesis and transfer of galactolipids in the chloroplast envelope membranes of Arabidopsis thaliana[END_REF]. NDGD1 is necessary for DGDG synthesis in the OE. Furthermore, NDGD1 binds PA and enables fusion of PA-containing liposomes in vitro [START_REF] Kelly | Synthesis and transfer of galactolipids in the chloroplast envelope membranes of Arabidopsis thaliana[END_REF]. Thus, it has been suggested that NDGD1 could facilitate lipid transport between both chloroplast membranes by triggering membrane-hemifusion [START_REF] Kelly | Synthesis and transfer of galactolipids in the chloroplast envelope membranes of Arabidopsis thaliana[END_REF]. Whether DGD1 acts as a tether or as a direct lipid transport protein remains to be determined.

Enzymes flipping lipids between membrane leaflets

Several recent studies suggest that enzymes involved in lipid translocation between membrane leaflets act as key players in non-vesicular lipid transport between membranes, notably by acting in concert with LTPs. Flippases can flip lipids against their concentration gradient in an ATPdependent manner to create asymmetric membranes while scramblases can translocate lipids between the two leaflets following their concentration gradient in an ATP-independent manner, thus, equilibrating lipids between membrane leaflets [START_REF] Maxfield | Intramembrane and Intermembrane Lipid Transport[END_REF]. The putative roles of these proteins in non-vesicular lipid exchanges might be 1) to ensure the selectivity and directionality of transport, 2) to facilitate the loading of lipids by LTPs, and/or 3) to facilitate the insertion of the transported lipid in the acceptor membrane [START_REF] Dziurdzik | The Vps13 Family of Lipid Transporters and Its Role at Membrane Contact Sites[END_REF][START_REF] Reinisch | Mechanisms of nonvesicular lipid transport[END_REF]. A good example of this mechanism is found in Gram-negative bacteria: lipopolysaccharide (LPS) is synthetized on the cytosolic leaflet of the IM and is subsequently transported to the extracellular leaflet of the OM [START_REF] Sperandeo | The lipopolysaccharide transport (Lpt) machinery : A nonconventional transporter for lipopolysaccharide assembly at the outer membrane of Gram-negative bacteria[END_REF]. LPS is first flipped across the IM by the flippase MsbA, then extracted from the IM by the LptB2FGC ABC transporter complex, ensuring the directionality of the transport. LPS transport through the periplasm is facilitated by LptACDFG proteins that form a hollow rod-like structure composed of hydrophobic β-jellyrolls reminiscent of the VPS13 hydrophobic groove [START_REF] Thélot | High-resolution views of lipopolysaccharide translocation driven by ABC transporters MsbA and LptB2FGC[END_REF]. The insertion of LPS in the OM and its translocation to the outer leaflet is ensured by the LptDE translocon [START_REF] Sperandeo | The lipopolysaccharide transport (Lpt) machinery : A nonconventional transporter for lipopolysaccharide assembly at the outer membrane of Gram-negative bacteria[END_REF]. A similar mechanism was proposed for lipid transport at ER-autophagosomes MCSs in yeast where the LTP Atg2 associates with the autophagosome-located Atg9 scramblase and with the ER-located scramblases TMEM41B and VMP1 [START_REF] Matoba | Atg9 is a lipid scramblase that mediates autophagosomal membrane expansion[END_REF][START_REF] Noda | Atg2 and Atg9 : Intermembrane and interleaflet lipid transporters driving autophagy[END_REF][START_REF] Orii | Transmembrane phospholipid translocation mediated by Atg9 is involved in autophagosome formation[END_REF]. Other LTPs, such as the human VPS13A or the yeast Osh6 protein have also been shown to associate with lipid scramblases [START_REF] D'ambrosio | Osh6 requires Ist2 for localization to ER-PM contacts and efficient phosphatidylserine transport in budding yeast[END_REF][START_REF] Park | XK is a partner for VPS13A : A molecular link between Chorea-Acanthocytosis and McLeod Syndrome[END_REF], suggesting further that lipid-flipping enzymes could play an active role in non-vesicular lipid transfer in association with LTPs.

In plants, lipid scramblases are also conserved but their role in lipid transport has never been investigated. However, in A. thaliana, a P4-ATPase flippase, ALA10, has been shown to regulate plastid MGDG synthesis in leaves (Table 8, Figure 3D(iii)) [START_REF] Botella | ALA10, a Phospholipid Flippase, Controls FAD2/FAD3 Desaturation of Phosphatidylcholine in the ER and Affects Chloroplast Lipid Composition in Arabidopsis thaliana[END_REF]. ALA10 is located in the ER where it can interact with the ALA-interacting subunits (ALIS) ALIS1 or ALIS5. This association regulates ALA10 subcellular localization: in the ER close to PM when ALA10 is co-expressed with ALIS1 or in the ER close to chloroplasts when co-expressed ALIS5 [START_REF] Botella | ALA10, a Phospholipid Flippase, Controls FAD2/FAD3 Desaturation of Phosphatidylcholine in the ER and Affects Chloroplast Lipid Composition in Arabidopsis thaliana[END_REF]. More recently, ALA10 localization was also shown to be impacted by its level of ubiquitination by the E3-Ubiquitin ligase PUB11, showing the complexity of the mechanisms regulating P4-ATPase localization in cells [START_REF] López-Marqués | Dynamic membranes : The multiple roles of P4 and P5 ATPases[END_REF][START_REF] Salvaing | PUB11-Dependent Ubiquitination of the Phospholipid Flippase ALA10 Modifies ALA10 Localization and Affects the Pool of Linolenic Phosphatidylcholine[END_REF]. Overexpression of ALA10 increases the ratio MGDG/PC in leaves and the 18:2 content in chloroplastic PC, suggesting it can stimulate MGDG synthesis and enrich 18:2-PC species in chloroplasts [START_REF] Botella | ALA10, a Phospholipid Flippase, Controls FAD2/FAD3 Desaturation of Phosphatidylcholine in the ER and Affects Chloroplast Lipid Composition in Arabidopsis thaliana[END_REF]. ALA10 interacts with the ER FA desaturase FAD2, involved in 18:1 acyl chain desaturation to 18:2, but not with FAD3, involved in 18:2 acyl chain desaturation to 18:3 [START_REF] Botella | ALA10, a Phospholipid Flippase, Controls FAD2/FAD3 Desaturation of Phosphatidylcholine in the ER and Affects Chloroplast Lipid Composition in Arabidopsis thaliana[END_REF]. Thus, it was proposed that ALA10, by interacting with FAD2, translocates PC species enriched in 18:2 from the lumenal to the cytosolic leaflet of the ER, promoting a local enrichment of this lipid and favouring its transport by an unknown mechanism to chloroplasts. To explain the higher MGDG/PC ratio in ALA10 overexpressing plants, the authors suggested that the translocated PC could be a substrate for phospholipases D to generate PA, a lipid known to activate MGD1 activity [START_REF] Botella | ALA10, a Phospholipid Flippase, Controls FAD2/FAD3 Desaturation of Phosphatidylcholine in the ER and Affects Chloroplast Lipid Composition in Arabidopsis thaliana[END_REF][START_REF] Dubots | Role of phosphatidic acid in plant galactolipid synthesis[END_REF]. This example illustrates that lipid flipping across membrane leaflets can also be involved in interorganellar lipid transfer in plants.

4 Lipid transport mediated by protein complexes 4.1 The TGD complex An important molecular effector implicated in ER to chloroplast lipid transport is the TGD (Trigalactosyldiacylglycerol) complex composed of at least five subunits: TGD1-5 (Table 8, Figure 3D(iv)). Plants deficient in any of the TGD proteins show substantial trigalactosyldiacylglycerol (TGDG) accumulation (hence their name) [START_REF] Xu | A permease-like protein involved in ER to thylakoid lipid transfer in Arabidopsis[END_REF], reduction in growth and photosynthetic capacity [START_REF] Li | Characterization of photosynthesis in Arabidopsis ER-to-plastid lipid trafficking mutants[END_REF][START_REF] Xu | Lipid Trafficking between the Endoplasmic Reticulum and the Plastid in Arabidopsis Requires the Extraplastidic TGD4 Protein[END_REF], and compromised embryogenesis [START_REF] Xu | Mutation of the TGD1 Chloroplast Envelope Protein Affects Phosphatidate Metabolism in Arabidopsis[END_REF]. Importantly, they show reduced amounts of C18 acyl chains in sn-2 position of chloroplast lipids, consistent with an Eukaryotic lipid import defect into chloroplasts [START_REF] Xu | A permease-like protein involved in ER to thylakoid lipid transfer in Arabidopsis[END_REF][START_REF] Xu | Lipid Trafficking between the Endoplasmic Reticulum and the Plastid in Arabidopsis Requires the Extraplastidic TGD4 Protein[END_REF]. TGD1, TGD2 and TGD3 form a non-canonical ABC transporter system at the chloroplast IE. It probably derives from a Gram-negative bacterial ABC import system that was present in cyanobacteria prior to endosymbiosis [START_REF] Roston | TGD1, -2, and -3 Proteins Involved in Lipid Trafficking Form ATP-binding Cassette (ABC) Transporter with Multiple Substrate-binding Proteins[END_REF]. Bacterial ABC importers are divided into two structural categories but show conserved features comprising 1) two TM domains composed of multiple transmembrane helices forming a permease to allow substrate passage, 2) two nucleotide binding domains specialized in ATP hydrolysis that provide energy for substrate transport and 3) a usually periplasmic substrate binding domain (SBD) that captures and delivers the substrate to the transporter subunits [START_REF] Beis | Structural basis for the mechanism of ABC transporters[END_REF][START_REF] Ford | Learning the ABCs one at a time : Structure and mechanism of ABC transporters[END_REF][START_REF] Hollenstein | Structure and mechanism of ABC transporter proteins[END_REF][START_REF] Wilkens | Structure and mechanism of ABC transporters[END_REF]. TGD1 structure prediction is reminiscent of a half-permease unit of a bacterial ABC importer harbouring six transmembrane helices and is therefore thought to be the permease subunit of the TGD1-3 complex [START_REF] Xu | A permease-like protein involved in ER to thylakoid lipid transfer in Arabidopsis[END_REF][START_REF] Xu | Mutation of the TGD1 Chloroplast Envelope Protein Affects Phosphatidate Metabolism in Arabidopsis[END_REF]. Consistent with its putative role, TGD1 is an integral membrane protein localized in the chloroplast IE [START_REF] Xu | Mutation of the TGD1 Chloroplast Envelope Protein Affects Phosphatidate Metabolism in Arabidopsis[END_REF]. TGD2 is the SBD-containing subunit of the TGD1-3 complex. In contrast to bacterial SBD subunits, TGD2 is anchored to the chloroplast IE by a Nterminal TM domain while the C-terminal part of the protein is located in the intermembrane space and specifically binds PA [START_REF] Awai | A phosphatidic acid-binding protein of the chloroplast inner envelope membrane involved in lipid trafficking[END_REF][START_REF] Lu | A 25-Amino Acid Sequence of the Arabidopsis TGD2 Protein Is Sufficient for Specific Binding of Phosphatidic Acid[END_REF][START_REF] Roston | Arabidopsis chloroplast lipid transport protein TGD2 disrupts membranes and is part of a large complex : TGD2 involved in chloroplast lipid transport[END_REF]. A mycobacterial cell entry (MCE) domain is juxtaposed to the TM domain [START_REF] Awai | A phosphatidic acid-binding protein of the chloroplast inner envelope membrane involved in lipid trafficking[END_REF]. Interestingly, bacterial MCE proteins are known to assemble into hexamers forming an elongated hydrophobic channel ideal for lipid transport between the bacterial OM and IM [START_REF] Ekiert | Architectures of Lipid Transport Systems for the Bacterial Outer Membrane[END_REF]. A 25 amino acid sequence partially overlapping the MCE domain is sufficient to mediate PA binding, but the complete TGD2 Cterminus still provides better binding affinity suggesting the existence of multiple binding determinants [START_REF] Lu | A 25-Amino Acid Sequence of the Arabidopsis TGD2 Protein Is Sufficient for Specific Binding of Phosphatidic Acid[END_REF]. TGD3 is a small ATPase that provides the energy for the TGDmediated lipid transport [START_REF] Lu | A Small ATPase Protein of Arabidopsis, TGD3, Involved in Chloroplast Lipid Import[END_REF]. TGD3 is a stromal protein that is associated with the chloroplast IE, consistent with its bacterial ABC importer counterparts (Figure 3D(iv)) [START_REF] Lu | A Small ATPase Protein of Arabidopsis, TGD3, Involved in Chloroplast Lipid Import[END_REF]. TGD1-3 form a highly stable complex of about 500 kDa presumably composed of two TGD1 permease subunits, two TGD3 ATPase subunits and between 8 and 12 TGD2 SBD subunits [START_REF] Roston | Arabidopsis chloroplast lipid transport protein TGD2 disrupts membranes and is part of a large complex : TGD2 involved in chloroplast lipid transport[END_REF][START_REF] Roston | TGD1, -2, and -3 Proteins Involved in Lipid Trafficking Form ATP-binding Cassette (ABC) Transporter with Multiple Substrate-binding Proteins[END_REF]. The large number of TGD2 proteins is surprising as it diverges from the canonical bacterial ABC importer architecture that usually contain only one SBD subunit. Why the TGD1-3 complex contains multiple SBD subunits is still unclear. Since TGD2 binds its putative substrate, PA, in a cooperative manner [START_REF] Lu | A 25-Amino Acid Sequence of the Arabidopsis TGD2 Protein Is Sufficient for Specific Binding of Phosphatidic Acid[END_REF], it has been suggested that an increased amount of SBDs could help to sense and bind PA even at extremely low concentrations [START_REF] Roston | TGD1, -2, and -3 Proteins Involved in Lipid Trafficking Form ATP-binding Cassette (ABC) Transporter with Multiple Substrate-binding Proteins[END_REF]. Alternatively, it has been proposed that the assembly of multiple SBDs could concentrate PA, a nonbilayer forming lipid, and thus facilitate lipid extraction from the donor membrane [START_REF] Labrant | Lipid transport required to make lipids of photosynthetic membranes[END_REF]. Consistent with the latter hypothesis, TGD2 has been found to disrupt membranes in vitro [START_REF] Roston | Arabidopsis chloroplast lipid transport protein TGD2 disrupts membranes and is part of a large complex : TGD2 involved in chloroplast lipid transport[END_REF]. Furthermore, the MCE domain contained in TGD2 suggests that its oligomerization might form a lipid transport channel like MlaD in the bacterial non-canonical ABC lipid transporter [START_REF] Chi | Structural mechanism of phospholipids translocation by MlaFEDB complex[END_REF][START_REF] Ekiert | Architectures of Lipid Transport Systems for the Bacterial Outer Membrane[END_REF][START_REF] Thong | Defining key roles for auxiliary proteins in an ABC transporter that maintains bacterial outer membrane lipid asymmetry[END_REF].

The TGD complex also harbours two additional proteins: TGD4 and TGD5. TGD4 is a β-barrel protein that forms homodimers in the chloroplast OE (Figure 3D(iv)) (Wang et al., 2012[START_REF] Wang | The Phosphatidic Acid Binding Site of the Arabidopsis Trigalactosyldiacylglycerol 4 (TGD4) Protein Required for Lipid Import into Chloroplasts[END_REF][START_REF] Xu | Lipid Trafficking between the Endoplasmic Reticulum and the Plastid in Arabidopsis Requires the Extraplastidic TGD4 Protein[END_REF]. TGD4 is distantly related to the lipid A transporter D (LptD) subunit that transports LPS from the bacterial IM to the bacterial OM (see above). Even though TGD4 was initially thought to be localized in the ER, further investigations indicate a localization in the chloroplast OE (Wang et al., 2012;[START_REF] Xu | Lipid Trafficking between the Endoplasmic Reticulum and the Plastid in Arabidopsis Requires the Extraplastidic TGD4 Protein[END_REF]. Thus, it has been proposed that TGD4 could be present at ER-chloroplast MCSs, thus providing a direct lipid transport route from the ER to the chloroplast (Wang & Benning, 2012). TGD4 binds PA with two cytosol-facing N-terminal domains that are both necessary and sufficient for lipid import, supporting a lipid transport function within the TGD complex (Wang et al., 2012[START_REF] Wang | The Phosphatidic Acid Binding Site of the Arabidopsis Trigalactosyldiacylglycerol 4 (TGD4) Protein Required for Lipid Import into Chloroplasts[END_REF]. Another β-barrel protein, AtLPTD1, homologous to LptD like TGD4, is present in the chloroplast OE (Figure 3D(iv)) [START_REF] Hsueh | The plastid outer membrane localized LPTD1 is important for glycerolipid remodelling under phosphate starvation : LptD orthologues in A. thaliana[END_REF]. Mutants depleted in AtLPTD1 show phenotypic traits similar to tgd mutants, including TGDG accumulation [START_REF] Hsueh | The plastid outer membrane localized LPTD1 is important for glycerolipid remodelling under phosphate starvation : LptD orthologues in A. thaliana[END_REF][START_REF] Labrant | Lipid transport required to make lipids of photosynthetic membranes[END_REF]. AtLPTD1 is expressed during plant adaptation to Pi starvation and is presumably implicated in DAG import into chloroplasts [START_REF] Hsueh | The plastid outer membrane localized LPTD1 is important for glycerolipid remodelling under phosphate starvation : LptD orthologues in A. thaliana[END_REF]. It is presently not known if AtLPTD1 is part of the TGD complex. TGD5 is a small glycine-rich protein interacting with the TGD1-3 complex and TGD4, strongly suggesting that it bridges the TGD complex subunits located in both chloroplast envelope membranes [START_REF] Fan | Arabidopsis TRIGALACTOSYLDIACYLGLYCEROL5 Interacts with TGD1, TGD2, and TGD4 to Facilitate Lipid Transfer from the Endoplasmic Reticulum to Plastids[END_REF]. A recent study showed that A. thaliana TGD5 mutants have a strong increase in plastid stromules [START_REF] Itoh | TGD5 is required for normal morphogenesis of non-mesophyll plastids, but not mesophyll chloroplasts, in Arabidopsis[END_REF]. Since stromules are known to promote ER-chloroplast contact sites [START_REF] Schattat | Correlated behavior implicates stromules in increasing the interactive surface between plastids and ER tubules[END_REF], it is tempting to hypothesize that stromule formation is the response to a lipid import defect caused by the lack of TGD5 subunit.

The current picture of the TGD complex suggests that ER-synthesized lipids in the chloroplast are directly channeled through the chloroplast OE and IE by TGD4 and TGD1-3, respectively (Figure 3D(iv)). A big gap of knowledge still concerns the nature of the transported lipid [START_REF] Labrant | Lipid transport required to make lipids of photosynthetic membranes[END_REF][START_REF] Michaud | Lipid Trafficking at Membrane Contact Sites During Plant Development and Stress Response[END_REF]. Since TGD2 and TGD4 have been shown to bind PA [START_REF] Awai | A phosphatidic acid-binding protein of the chloroplast inner envelope membrane involved in lipid trafficking[END_REF]Wang et al., 2012), it is tempting to speculate that PA is the transported lipid. However, a mathematical model mimicking chloroplast lipid synthesis via the Eukaryotic pathway suggests the import of DAG rather than PA (Maréchal & Bastien, 2014). Thus, PA could have a regulatory function of TGD, as it is the case for MGD1 for instance [START_REF] Dubots | Role of phosphatidic acid in plant galactolipid synthesis[END_REF]. Remaining unanswered questions concern the connection between the TGD complex and the ER and its putative involvement in precursors import from the ER to the OE.

The MTL complex

The MTL complex is a complex involved in mitochondrial lipid transport, notably in response to Pi starvation [START_REF] Michaud | Analysis of the MTL Supercomplex at Contact Sites Between Mitochondria and Plastids[END_REF][START_REF] Michaud | AtMic60 Is Involved in Plant Mitochondria Lipid Trafficking and Is Part of a Large Complex[END_REF]. The MTL complex is a huge lipid-containing entity with roughly 200 proteins and migrating at about 800 kDa on native gel [START_REF] Michaud | AtMic60 Is Involved in Plant Mitochondria Lipid Trafficking and Is Part of a Large Complex[END_REF]. Proteomic analysis revealed that the MTL complex contains mainly mitochondrial proteins and also several proteins located in non-mitochondrial compartments, such as the plastid OE, suggesting a possible location at mitochondrial MCSs. Interestingly, all the components of the translocase of the outer membrane (TOM) complex and AtMic60 are present in the MTL complex (Table 8, Figure 3C(ii)). AtMic60 is a confirmed functional homolog of yeast Mic60, a core component of the mitochondrial contact site cristae organizing system (MICOS) complex [START_REF] Pfanner | Uniform nomenclature for the mitochondrial contact site and cristae organizing system[END_REF].

MICOS plays a central role in mitochondrial membrane architecture, dynamics of protein import, lipid homeostasis and lipid trafficking [START_REF] Michaud | Glycerolipid synthesis and lipid trafficking in plant mitochondria[END_REF][START_REF] Mukherjee | MICOS and the mitochondrial inner membrane morphology -when things get out of shape[END_REF][START_REF] Rampelt | Role of the mitochondrial contact site and cristae organizing system in membrane architecture and dynamics[END_REF]. In yeast and mammals, Mic60, a core component located in the IM, interacts with multiple partners in the mitochondrial OM, i.e. the TOM complex, SAM50, VDAC and DNAJC11, thus tightly tethering the mitochondrial OM and IM [START_REF] Mukherjee | MICOS and the mitochondrial inner membrane morphology -when things get out of shape[END_REF]. AtMic60 interacts with AtTom40 and a decrease in AtTom40 content was observed in the MTL complex of atmic60 mutants, suggesting that AtMic60 also modulates OM-IM tethering [START_REF] Michaud | AtMic60 Is Involved in Plant Mitochondria Lipid Trafficking and Is Part of a Large Complex[END_REF]. Furthermore, the abundance of AtMic60-AtTom40 in the MTL complex increases in Pi deprived conditions, suggesting a role in lipid remodeling [START_REF] Michaud | AtMic60 Is Involved in Plant Mitochondria Lipid Trafficking and Is Part of a Large Complex[END_REF]. Lipid analysis of the MTL complex in atmic60 KO lines revealed that DGDG accumulation in the MTL complex is compromised whereas PE accumulates during Pi starvation, suggesting that PE export and DGDG import are impaired (Figure 3C(ii)). A role in intra-mitochondrial lipid trafficking was further supported by mitochondrial lipid analyses showing a decreased DGDG and increased PE levels in atmic60 compared to WT during Pi starvation [START_REF] Michaud | AtMic60 Is Involved in Plant Mitochondria Lipid Trafficking and Is Part of a Large Complex[END_REF]. AtMic60 also destabilizes liposomes in vitro, suggesting that it could promote lipid desorption from membranes prior to transport [START_REF] Michaud | AtMic60 Is Involved in Plant Mitochondria Lipid Trafficking and Is Part of a Large Complex[END_REF]. Even if AtMic60 and AtTom40 were identified as key players, the exact lipid transport mechanism exerted by the MTL complex as a whole, as well as the role of its partners, remains to be unravelled. Since the MTL complex also encloses several extra-mitochondrial proteins, notably chloroplast OE proteins of unknown function, it is tempting to speculate that the MTL complex might form a structure connecting mitochondrial membranes to other cell compartments such as chloroplasts, promoting direct lipid transport between both compartments [START_REF] Michaud | AtMic60 Is Involved in Plant Mitochondria Lipid Trafficking and Is Part of a Large Complex[END_REF][START_REF] Michaud | Glycerolipid synthesis and lipid trafficking in plant mitochondria[END_REF]. Such a hypothetical structure is reminiscent of the ER-mitochondria organizing network (ERMIONE) that has been suggested to organize ER-mitochondria MCSs functions in yeast and mammals and to be involved in ER to IM lipid transport [START_REF] Wideman | The evolution of ERMIONE in mitochondrial biogenesis and lipid homeostasis : An evolutionary view from comparative cell biology[END_REF].

Conclusion and perspectives

The general mechanisms described in mammals and yeast for non-vesicular glycerolipid transport are conserved in plants. For instance, most of the LTP families present in yeast and mammals are also found in plants, even if only a few of them have been characterized in terms of subcellular localization, lipid transport specificities and cellular functions. Peculiarities have to be highlighted concerning non-vesicular lipid transport in plants:

-Plants cope with a wide variety of stresses where lipid signaling and membrane remodeling play a crucial role in the adaptation process [START_REF] Hou | Lipid signalling in plant responses to abiotic stress : Lipid signalling in plant responses to abiotic stress[END_REF]Liu et al., 2019;[START_REF] Michaud | Lipid Trafficking at Membrane Contact Sites During Plant Development and Stress Response[END_REF]. Thus, specific lipid signaling and trafficking systems might have been developed during evolution to empower the plant response to these particular situations. In accordance with this, many LTP families are expanded in plants and most of them are highly responsive to biotic and abiotic stresses. In addition, most of the plant LTPs characterized until now have a confirmed role in plant stress susceptibility (Table 1). It also has to be noticed that many A. thaliana LTP genes are predicted to be transcribed into several mRNA isoforms in the TAIR database, increasing the putative number of lipid transporter that could co-exist in a cell. -Plant have a chloroplast which biogenesis requires extensive exchanges of lipids with the ER.

Thus, specific lipid transport machineries, such as the TGD complex, have evolved during evolution to ensure chloroplast membranes biogenesis and functions. However, the mechanisms involved in ER-plastid MCSs formation and in the transport of lipids between both organelles remain poorly characterized. In addition, chloroplast lipids can be major contributors for the biogenesis of extra-plastidial membranes in stress conditions, such as Pi starvation where DGDG is exported to mitochondria, PM and vacuoles, or nitrogen starvation in legumes where symbiosome membrane formation requires DGDG. Beside the poorly understood mechanisms involved in those transports, the question of whether chloroplast glycerolipids could also be involved in extra-plastidial membrane synthesis in normal growth conditions remains open. -Finally, the synthesis cell wall structures in plants, such as cutin, wax or sporopollenin, requires the secretion to the extracellular space of hydrophobic components. To ensure this function, a specific family of LTPs, the nsLTPs, appeared in plants during evolution. In this huge family, some of them are also able to bind glycerolipids and are involved in membrane biogenesis during stress, highlighting that plants have evolved specific pathways for nonvesicular lipid transport.

In summary, the understanding of the processes involved in non-vesicular lipid transfer in plants is in its infancy. Many studies still have to be performed to understand how this process occurs and how it is regulated in response to stress. [START_REF] Hooper | SUBA4 : The interactive data analysis centre for Arabidopsis subcellular protein locations[END_REF][START_REF] Schwacke | ARAMEMNON, a novel database for Arabidopsis integral membrane proteins[END_REF]. The domain organization found for each protein is also indicated. HD: homeodomain, PH: pleckstrin homology domain, TM: transmembrane domain, ZIP: leucine zipper, ZLZ: leucine zipper-loop-zipper. [START_REF] Hooper | SUBA4 : The interactive data analysis centre for Arabidopsis subcellular protein locations[END_REF][START_REF] Schwacke | ARAMEMNON, a novel database for Arabidopsis integral membrane proteins[END_REF]. The domain organization found for each protein is also indicated. ORD: oxysterol-binding related domain, PH: pleckstrin homology domain.

FUNDINGS

LEGENDS TO FIGURES

Figure 1: Glycerolipid families found in plant cells. A. Glycerolipids are composed of a glycerol backbone esterified with two fatty acids (FA) in sn-1 and sn-2 positions. In Arabidopsis thaliana, the main FAs found in glycerolipids are 16 (C16) or 18 (C18) carbons-long and have up to three unsaturations (C16:0 to C16:3 and C18:0 to C18:3). In A. thaliana, the length of the carbon chain in sn-2 position defines the origin of the glycerolipid backbone: a C16 is a signature of a backbone synthesized by the plastid by the Prokaryotic pathway while a C18 is a signature of a backbone synthesized in the endoplasmic reticulum by the Eukaryotic pathway. B. Three main glycerolipid families are found in plants depending on the nature of the polar head located in sn-3 position of the glycerol backbone: 1) the phospholipids, all presenting a phosphate group in their polar head, 2) the galactoglycerolipids, having a polar head containing one or two galactose residues, and 3) the sulphoglycerolipid, with a sugar-based polar head containing a negatively charge sulfate group. Spontaneous transfer of glycerolipids between membranes. B-E. Lipid transport mediated by lipid transfer proteins (LTPs). LTPs have a soluble domain with a hydrophobic cavity accommodating lipid molecule(s). They can be soluble (B), membrane bound (C) or anchored at two membranes (D), to shuttle lipids between membranes, or they can adopt a bridge-like structure forming a hydrophobic tunnel for lipid channeling between membranes (E). F. Lipid transport can be mediated by multisubunits complexes crossing two or several membranes. G. Some membrane protein can promote non-vesicular lipid transport by favoring lipid extrusion or insertion from the donor or the acceptor membranes respectively. The different proteins and complexes using each mechanisms that will be discussed in this chapter are indicated.

Figure 2 :

 2 Figure 2: Mechanisms involved in non-vesicular glycerolipid transport at membrane contact sites. A.Spontaneous transfer of glycerolipids between membranes. B-E. Lipid transport mediated by lipid transfer proteins (LTPs). LTPs have a soluble domain with a hydrophobic cavity accommodating lipid molecule(s). They can be soluble (B), membrane bound (C) or anchored at two membranes (D), to shuttle lipids between membranes, or they can adopt a bridge-like structure forming a hydrophobic tunnel for lipid channeling between membranes (E). F. Lipid transport can be mediated by multisubunits complexes crossing two or several membranes. G. Some membrane protein can promote non-vesicular lipid transport by favoring lipid extrusion or insertion from the donor or the acceptor membranes respectively. The different proteins and complexes using each mechanisms that will be discussed in this chapter are indicated.

Figure 3 :

 3 Figure 3: Proteins involved in non-vesicular glycerolipid transport at different membrane contact sites (MCSs) in plant cells. A. Transport of diacylglycerol (DAG) by Syt1/3 at endoplasmic reticulum (ER)-plasma membrane (PM) MCSs. Syt1/3 are anchored to the ER by a transmembrane domain and to the PM by the binding of the C2 domains to phosphatidylinositides (PIPs). DAG transport is mediated by the synaptotagmin-like mitochondrial-lipid binding protein (SMP) domain. B. Putative transport of sitosterol by ORP3A at ER-golgi MCS. ORP3A interacts in the ER with the PVA12 VAP protein. C. (i) Putative transport of cardiolipin at mitochondrial (M) outer (OM)-inner (IM) membrane MCSs mediated by NDPK-3. NDPK-3 interacts in the IM with the ANT translocator. (ii) Digalactosyldiacylglycerol (DGDG) and phosphatidylethanolamine transport at OM-IM MCSs mediated by the mitochondrial transmembrane lipoprotein (MTL) complex during phosphate (Pi) starvation. In this complex, AtMic60 interacts with Tom40 and plays a key role in the lipid transport process. Because of the presence of chloroplast (C) proteins in the MTL complex, it could also be located at chloroplasts-mitochondria MCSs to mediate DGDG import during Pi starvation. D. Lipid transport at ER-chloroplast MCSs and outer (OE)-inner (IE) envelopes MCSs. (i) Putative lipid transport mediated by phosphatidylcholine (PC) remodeling at ER-chloroplasts MCSs. BnCLIP1 lipase could form lyso-PC from PC that could be acylated in the OE by lyso-PC acyltransferases (LPCAT) using a local pool of acyl-CoA generated by the long-chain acyl-CoA synthetases LACS4 and LACS9. (ii) The DGDG synthase DGD1 might play a role in OE-IE lipid transport thanks to its N-terminal extension. (iii) The ALA10 flippase could promote PC transport from the ER to the chloroplasts by promoting enrichment of 18:2-PC in the cytosolic leaflet of the ER. (iv) Import of lipids precursors in chloroplasts IE by the TGD complex and the LptD1 protein. TDG1, 2 and 3 form an ABC transporter in the IE

Table 4 :

 4 This work is supported by the French National Research Agency in the framework of the "investissement d'avenir" program (ANR-15-IDEX-O2) and of the ANRJCJC MiCoSLiT (ANR-19-C13-0013). It also received funding from GRAL a program from the Chemistry Biology Health (CBH) Graduate School of University Grenoble Alpes (ANR-17-EURE-0003). Genes of the StAR related transfers (StART) family present in the A. thaliana genome. Protein localization were determined experimentally or the consensus localizations from SUBA and ARAMEMNON websites (prediction) are indicated

	At2g34710 PHB, ATHB-14	Nucleus

Table 5 :

 5 Genes of the OSBP related protein (ORP) family present in the A. thaliana genome. Protein localization were determined experimentally or the consensus localizations from SUBA and ARAMEMNON websites (prediction) are indicated

	AGI	Name	Localization	Domain organization References
	At2g31020	ORP1A	Cyto/Chloro (prediction)	PH-ORD
	At2g31030	ORP1B	Cyto (prediction)	ORD
	At4g08180	ORP1C	Nucleus/Chloro (prediction)	PH-ORD
	At1g13170	ORP1D	Nucleus/Chloro (prediction)	PH-ORD
	At4g22540	ORP2A	Nucleus (prediction)	PH-ORD
	At4g12460	ORP2B	Nucleus (prediction)	PH-ORD
	At5g02100	ORP3A	ER	ORD	(Saravanan et al., 2009)
	At3g09300	ORP3B	Cyto (prediction)	ORD
	At5g59420	ORP3C	Cyto (prediction)	ORD
	At4g25860	ORP4A	Cyto (prediction)	ORD
	At4g25850	ORP4B	Cyto (prediction)	ORD
	At5g57240	ORP4C	Cyto (prediction)	ORD

TABLES

Roles

Characterized LTP proteins in plants Lipid transfer between membranes Syt1, Syt3, At1g73200, ORP3A, AtSfh1, AtPITP11, Ssh2, NbSec14

Membrane tethering Syt1, Syt 3, Syt5, Syt7, At1g73200 Signaling AtSfh1, Ssh1, AtPIPT7, MtN5

Vesicular trafficking Syt2, AtPATL1, AtPATL2, AtPITP7

Plant development PiORP3, AtSfh1, GhLTPG1

Abiotic stress response Syt1, Syt3, AtPATL1, Ssh1, AsE246, MtN5

Biotic stress response Syt1, Syt5, Syt7, VAD1, BAGP1, ERD2, ORPs, AtPATL3, AtPATL6, NbSec14

Reguation of gene expression Syt7, GL2, HD-StART, GmOSBP [START_REF] Hooper | SUBA4 : The interactive data analysis centre for Arabidopsis subcellular protein locations[END_REF][START_REF] Schwacke | ARAMEMNON, a novel database for Arabidopsis integral membrane proteins[END_REF]. The domain organization found for each protein is also indicated. CC: coiled-coil domain, PH: pleckstrin homology domain, TM: transmembrane domain. Table 7: Genes of the Sec14 super-family present in the A. thaliana genome. Protein localization were determined experimentally or the consensus localizations from SUBA and ARAMEMNON websites (prediction) are indicated [START_REF] Hooper | SUBA4 : The interactive data analysis centre for Arabidopsis subcellular protein locations[END_REF][START_REF] Schwacke | ARAMEMNON, a novel database for Arabidopsis integral membrane proteins[END_REF]. The domain organization found for each protein is also indicated. GOLD: Golgi dynamic.

AGI Name

Localization References At4g11010 NDPK3a Mitochondria/plastids [START_REF] Carrie | Approaches to defining dual-targeted proteins in Arabidopsis[END_REF][START_REF] Hammargren | On the phylogeny, expression and targeting of plant nucleoside diphosphate kinases[END_REF][START_REF] Luzarowski | Affinity purification with metabolomic and proteomic analysis unravels diverse roles of nucleoside diphosphate kinases[END_REF] [START_REF] Hooper | SUBA4 : The interactive data analysis centre for Arabidopsis subcellular protein locations[END_REF][START_REF] Schwacke | ARAMEMNON, a novel database for Arabidopsis integral membrane proteins[END_REF].

whereas TGD5 bridges the IE and OE via its interaction with TGD1/2/3 and TGD4. LptD1 is a homolog of TGD4 and might be involved in galactoglycerolipid synthesis during Pi starvation.