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• W2100021650 abstract "In eukaryotes, phosphatidylserine (PtdSer) can serve as a precursor of phosphatidylethanolamine (PtdEtn) and phosphatidylcholine (PtdCho), which are the major cellular phospholipids. PtdSer synthesis originates in the endoplasmic reticulum (ER) and its subdomain named the mitochondria-associated membrane (MAM). PtdSer is transported to the mitochondria in mammalian cells and yeast, and decarboxylated by PtdSer decarboxylase 1 (Psd1p) to form PtdEtn. A second decarboxylase, Psd2p, is also found in yeast in the Golgi-vacuole. PtdEtn produced by Psd1p and Psd2p can be transported to the ER, where it is methylated to form PtdCho. Organelle-specific metabolism of the aminoglycerophospholipids is a powerful tool for experimentally following lipid traffic that is now enabling identification of new proteins involved in the regulation of this process. Genetic and biochemical experiments demonstrate that transport of PtdSer between the MAM and mitochondria is regulated by protein ubiquitination, which affects events at both membranes. Similar analyses of PtdSer transport to the locus of Psd2p now indicate that a membrane-bound phosphatidylinositol transfer protein and the C2 domain of Psd2p are both required on the acceptor membrane for efficient transport of PtdSer.Collectively, these recent findings indicate that novel multiprotein assemblies on both donor and acceptor membranes participate in interorganelle phospholipid transport. In eukaryotes, phosphatidylserine (PtdSer) can serve as a precursor of phosphatidylethanolamine (PtdEtn) and phosphatidylcholine (PtdCho), which are the major cellular phospholipids. PtdSer synthesis originates in the endoplasmic reticulum (ER) and its subdomain named the mitochondria-associated membrane (MAM). PtdSer is transported to the mitochondria in mammalian cells and yeast, and decarboxylated by PtdSer decarboxylase 1 (Psd1p) to form PtdEtn. A second decarboxylase, Psd2p, is also found in yeast in the Golgi-vacuole. PtdEtn produced by Psd1p and Psd2p can be transported to the ER, where it is methylated to form PtdCho. Organelle-specific metabolism of the aminoglycerophospholipids is a powerful tool for experimentally following lipid traffic that is now enabling identification of new proteins involved in the regulation of this process. Genetic and biochemical experiments demonstrate that transport of PtdSer between the MAM and mitochondria is regulated by protein ubiquitination, which affects events at both membranes. Similar analyses of PtdSer transport to the locus of Psd2p now indicate that a membrane-bound phosphatidylinositol transfer protein and the C2 domain of Psd2p are both required on the acceptor membrane for efficient transport of PtdSer. Collectively, these recent findings indicate that novel multiprotein assemblies on both donor and acceptor membranes participate in interorganelle phospholipid transport. Intracellular phospholipid transport in eukaryotes is one of the most fundamental aspects of organelle biogenesis, yet it remains poorly understood with respect to the genes that are involved in the process and the mechanism of action of the gene products. Most phospholipid synthesis originates in the endoplasmic reticulum (ER) and these lipids must be disseminated throughout the cell for the assembly of new organelles (1Bell R.M. Ballas L.M. Coleman R.A. Lipid topogenesis.J. Lipid Res. 1981; 22: 391-403Google Scholar, 2Paltauf F. Kohlwein S.D. Henry S.A. Regulation and compartmentalization of lipid synthesis in yeast.in: Jones E.W. Pringle J.R. Broach J.R. The Molecular and Cellular Biology of the Yeast Saccharomyces. Vol. 2. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1992: 415-500Google Scholar). Five of the most prominent phospholipids synthesized in the ER (in decreasing order of abundance) are phosphatidylcholine (PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer), and phosphatidic acid (PtdOH). Although the pool size of PtdOH is usually only 1–2% of the ER membrane lipid, the flux through this pool is extremely high, since it primarily functions as a precursor for all the other phospholipids and triacylglycerol. The role of the ER in phospholipid synthesis is dominant but not exclusive. Significant rates of PtdCho and PtdIns synthesis can also occur in the Golgi (3Vance J.E. Vance D.E. Does rat liver Golgi have the capacity to synthesize phospholipids for lipoprotein secretion?.J. Biol. Chem. 1988; 263: 5898-5909Google Scholar, 4Henneberry A.L. Wright M.M. McMaster C.R. The major sites of cellular phospholipid synthesis and molecular determinants of Fatty Acid and lipid head group specificity.Mol. Biol. Cell. 2002; 13: 3148-3161Google Scholar, 5Leber A. Hrastnik C. Daum G. Phospholipid-synthesizing enzymes in Golgi membranes of the yeast, Saccharomyces cerevisiae.FEBS Lett. 1995; 377: 271-274Google Scholar). In addition, the mitochondria can synthesize their own pool of PtdOH that is believed to function as an important major precursor for mitochondrial phosphatidylglycerol (PtdGro) and cardiolipin (Ptd2Gro) (6Chakraborty T.R. Vancura A. Balija V.S. Haldar D. Phosphatidic acid synthesis in mitochondria. Topography of formation and transmembrane migration.J. Biol. Chem. 1999; 274: 29786-29790Google Scholar). Both PtdGro and Ptd2Gro are retained within the mitochondria of most eukaryotic cells. Following synthesis, the phospholipids must be transported to membranes that lack the synthetic machinery to generate their own full repertoire of lipids. In Fig. 1, selective aspects of interorganelle glycerophospholipid traffic, which are the major focus of this review, are shown. Mitochondria must import PtdCho, PtdIns, and PtdSer. The PtdSer imported into mitochondria is rapidly metabolized to PtdEtn by PtdSer decarboxylase 1 (Psd1p) (7Voelker D.R. Phosphatidylserine functions as the major precursor of phosphatidylethanolamine in cultured BHK 21 cells.Proc. Natl. Acad. Sci. USA. 1984; 81: 2669-2673Google Scholar, 8Voelker D.R. Reconstitution of phosphatidylserine import into rat liver mitochondria.J. Biol. Chem. 1989; 264: 8019-8025Google Scholar). The PtdEtn produced within the mitochondria is essential for the function of the organelle (9Birner R. Burgermeister M. Schneiter R. Daum G. Roles of phosphatidylethanolamine and of its several biosynthetic pathways in Saccharomyces cerevisiae.Mol. Biol. Cell. 2001; 12: 997-1007Google Scholar, 10Storey M.K. Clay K.L. Kutateladze T. Murphy R.C. Overduin M. Voelker D.J. Phosphatidylethanolamine has an essential role in Saccharomyces cerevisiae that is independent of its ability to form hexagonal phase structures.J. Biol. Chem. 2001; 276: 48539-48548Google Scholar). PtdEtn produced in the ER by the Kennedy pathway (i.e., the sequential conversion of ethanolamine → phosphoethanolamine → CDP-ethanolamine → PtdEtn) (11Kennedy E.P. Weiss S.B. The function of cytidine coenzymes in the biosynthesis of phospholipids.J. Biol. Chem. 1956; 222: 193-214Google Scholar) is only poorly transported-imported into mitochondria, and cannot substitute for the essential function of the pool produced within the mitochondria (9Birner R. Burgermeister M. Schneiter R. Daum G. Roles of phosphatidylethanolamine and of its several biosynthetic pathways in Saccharomyces cerevisiae.Mol. Biol. Cell. 2001; 12: 997-1007Google Scholar, 10Storey M.K. Clay K.L. Kutateladze T. Murphy R.C. Overduin M. Voelker D.J. Phosphatidylethanolamine has an essential role in Saccharomyces cerevisiae that is independent of its ability to form hexagonal phase structures.J. Biol. Chem. 2001; 276: 48539-48548Google Scholar, 12Trotter P.J. Voelker D.R. Identification of a non-mitochondrial phosphatidylserine decarboxylase activity (PSD2) in the yeast Saccharomyces cerevisiae.J. Biol. Chem. 1995; 270: 6062-6070Google Scholar). Quite remarkably, the PtdEtn produced by Psd1p within the mitochondria is not static and restricted to this organelle, but can be exported to all other membranes of eukaryotes to fulfill their requirement for PtdEtn (13Voelker D.R. Interorganelle transport of aminoglycerophospholipids.Biochim. Biophys. Acta. 2000; 1486: 97-107Google Scholar). In eukaryotes such as yeast that can efficiently methylate PtdEtn to PtdCho in the ER (2Paltauf F. Kohlwein S.D. Henry S.A. Regulation and compartmentalization of lipid synthesis in yeast.in: Jones E.W. Pringle J.R. Broach J.R. The Molecular and Cellular Biology of the Yeast Saccharomyces. Vol. 2. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1992: 415-500Google Scholar), the flux of PtdSer into the mitochondria, and PtdEtn out of the mitochondria, can be used to generate all of the PtdEtn and PtdCho required for all cell membranes. These findings clearly indicate that mitochondria have the capacity to produce large amounts of phospholipid and play a very dynamic role in the biogenesis of other cell membranes. The Golgi apparatus has a limited capacity to synthesize some phospholipids (3Vance J.E. Vance D.E. Does rat liver Golgi have the capacity to synthesize phospholipids for lipoprotein secretion?.J. Biol. Chem. 1988; 263: 5898-5909Google Scholar, 4Henneberry A.L. Wright M.M. McMaster C.R. The major sites of cellular phospholipid synthesis and molecular determinants of Fatty Acid and lipid head group specificity.Mol. Biol. Cell. 2002; 13: 3148-3161Google Scholar, 5Leber A. Hrastnik C. Daum G. Phospholipid-synthesizing enzymes in Golgi membranes of the yeast, Saccharomyces cerevisiae.FEBS Lett. 1995; 377: 271-274Google Scholar), but is generally thought to require the transport of PtdEtn, PtdIns, and PtdSer in most eukaryotes. It remains unclear how much of the requirement for PtdCho and PtdIns is fulfilled autonomously by the organelle and how much must be transported from the ER. In both lower and higher eukaryotes, the availability of choline enables the Kennedy pathway (choline → phosphocholine → CDP-choline → PtdCho) to be used for PtdCho synthesis in the ER and Golgi. In yeast, PtdSer transported to the Golgi can also be a substrate for PtdSer decarboxylase 2 (Psd2p) (12Trotter P.J. Voelker D.R. Identification of a non-mitochondrial phosphatidylserine decarboxylase activity (PSD2) in the yeast Saccharomyces cerevisiae.J. Biol. Chem. 1995; 270: 6062-6070Google Scholar). The Psd2p is also found to colocalize with the vacuole compartment in yeast. The flux of PtdSer through the Golgi-vacuole is also quite high. The resultant PtdEtn can fulfill most cellular needs for this lipid, but is incompetent to supply the pool required by mitochondria under respiratory conditions (9Birner R. Burgermeister M. Schneiter R. Daum G. Roles of phosphatidylethanolamine and of its several biosynthetic pathways in Saccharomyces cerevisiae.Mol. Biol. Cell. 2001; 12: 997-1007Google Scholar, 10Storey M.K. Clay K.L. Kutateladze T. Murphy R.C. Overduin M. Voelker D.J. Phosphatidylethanolamine has an essential role in Saccharomyces cerevisiae that is independent of its ability to form hexagonal phase structures.J. Biol. Chem. 2001; 276: 48539-48548Google Scholar). When required, the PtdEtn produced in the Golgi-vacuole can also be transported to the ER for methylation to PtdCho, and fulfill all the cellular needs for these two lipids under nonrespiratory conditions (glucose medium) (12Trotter P.J. Voelker D.R. Identification of a non-mitochondrial phosphatidylserine decarboxylase activity (PSD2) in the yeast Saccharomyces cerevisiae.J. Biol. Chem. 1995; 270: 6062-6070Google Scholar). The plasma membrane, lysosomes, and endosomes appear essentially incapable of the synthesis of PtdCho, PtdEtn, PtdIns, and PtdSer (14Van Golde L.M.G. Raben J. Batenburg J.J. Fleischer B. Zambrano F. Fleischer S. Biosynthesis of lipids in Golgi complex and other subcellular fractions from rat liver.Biochim. Biophys. Acta. 1974; 360: 179-192Google Scholar). Compositional analyses of these membranes reveal that they all contain the aforementioned lipids (15Colbeau A. Nachbaur J. Vignais P.M. Enzymic characterization and lipid composition of rat liver subcellular membranes.Biochim. Biophys. Acta. 1971; 249: 462-492Google Scholar, 16Kobayashi T. Beuchat M.H. Chevallier J. Makino A. Mayran N. Escola J.M. Lebrand C. Cosson P. Gruenberg J. Separation and characterization of late endosomal membrane domains.J. Biol. Chem. 2002; 277: 32157-32164Google Scholar). Thus, the biogenesis of these membranes and the maintenance of their structural and functional integrity require lipid transport. For many years, phospholipid transfer-exchange proteins were proposed as likely candidates for executing lipid transport reactions required for new membrane assembly (17Wirtz K.W.A. Phospholipid transfer proteins.Annu. Rev. Biochem. 1991; 60: 73-99Google Scholar). However, convincing evidence that these proteins are primary effectors for de novo membrane assembly has not been forthcoming. In addition, critical genetic tests of the function of these proteins have failed to establish an essential role as soluble carriers of phospholipid for the purpose of membrane biogenesis (18Alb J.G. Gedvilarte A. Cartee R.T. Skinner H.B. Bankaitis V.A. Mutant rat phosphotidylinositol/phosphatidylcholine transfer proteins specifically defective in phosphotidylinositol transfer: implications for the regulation of phospholipid transfer activity.Proc. Natl. Acad. Sci. USA. 1995; 92: 8826-8830Google Scholar, 19Seedorf U. Ellinghaus P. Nofer J.R. Sterol carrier protein-2.Biochim. Biophys. Acta. 2000; 1486: 45-54Google Scholar, 20van Helvoort A. de Brouwer A. Ottenhoff R. Brouwers J.F. Wijnholds J. Beijnen J.H. Rijneveld A. van der Poll T. van der Valk M.A. Majoor D. Voorhout W. Wirtz K.W. Elferink R.P. Borst P. Mice without phosphatidylcholine transfer protein have no defects in the secretion of phosphatidylcholine into bile or into lung airspaces.Proc. Natl. Acad. Sci. USA. 1999; 96: 11501-11506Google Scholar). One of the most extensively studied phospholipid transfer proteins is the PtdCho-PtdIns transfer protein in yeast named Sec14p (21Aitken J. van Heusden G.P.H. Temkin M. Dowhan W. The gene encoding the phosphatidylinositol transfer protein is essential for cell growth.J. Biol. Chem. 1990; 265: 4711-4717Google Scholar). Current evidence suggests that Sec14p acts principally as a regulator of PtdCho synthesis, especially in the Golgi apparatus (22Li X. Xie Z. Bankaitis V.A. Phosphatidylinositol/phosphatidylcholine transfer proteins in yeast.Biochim. Biophys. Acta. 2000; 1486: 55-71Google Scholar). In many independent studies of transport of newly synthesized phospholipids between organelles, classical inhibitors of vesicle traffic have proven ineffective at arresting the process. Monensin (a disruptor of protein traffic through the Golgi) failed to alter PtdCho transport from the ER to the plasma membrane (23Kaplan M.R. Simoni R.D. Intracellular transport of phosphatidylcholine to the plasma membrane.J. Cell Biol. 1985; 101: 441-445Google Scholar). In these same studies, the cytoskeletal poisons nocodazole and colchicine, as well as ATP depletion, were also without measurable effect. Similar findings were also reported for PtdEtn transport between the ER and the plasma membrane (24Sleight R.G. Pagano R.E. Rapid appearance of newly synthesized phosphatidylethanolamine at the plasma membrane.J. Biol. Chem. 1983; 258: 9050-9058Google Scholar). Additional lines of investigation examining PtdEtn export from the mitochondria to the plasma membrane found this process was insensitive to brefeldin A intoxication (25Vance J.E. Aasman E.J. Szarka R. Brefeldin A does not inhibit the movement of phosphatidylethanolamine from its site of synthesis to the cell surface.J. Biol. Chem. 1991; 266: 8241-8247Google Scholar), which disrupts Golgi structure and function. Genetic experiments using yeast temperature-sensitive sec14 mutants also provide results that indicate PtdIns traffic between the ER and the plasma membrane is not altered under nonpermissive conditions (37°C) that block protein transport through the Golgi (26Gnamusch E. Kalaus C. Hrastnik C. Paltauf F. Daum G. Transport of phospholipids between subcellular membranes of wild-type yeast cells and of the phosphatidylinositol transfer protein-deficient strain Saccharomyces cerevisiae sec 14.Biochim. Biophys. Acta. 1992; 1111: 120-126Google Scholar). Experiments examining PtdSer transport between the ER and the mitochondria in permeabilized cells also demonstrate the process is insensitive to agents that can disrupt vesicle traffic, such as GTPγS (27Voelker D.R. Characterization of phosphatidylserine synthesis and translocation in permeabilized animal cells.J. Biol. Chem. 1990; 265: 14340-14346Google Scholar). Collectively, these findings indicate that the transport of phospholipids between organelles can follow some specialized and poorly defined routes that are different from those followed by membrane proteins. This observation is surprising because phospholipids must necessarily accompany proteins in vesicle budding and fusion events. However, the majority of existing evidence indicates that when membrane protein traffic is arrested by either genetic manipulation or the use of metabolic poisons, traffic of newly synthesized glycerophospholipids, in most cases, proceeds unabated. These findings indicate that novel processes that are independent of membrane protein traffic must regulate the interorganelle movement of many phospholipids. One potential route for phospholipid transport that could account for the above observations is lipid movement via specialized zones of apposition that occur between different subcellular membranes. Several morphological studies performed decades ago identified specialized regions of close association of mitochondria with the ER (28Franke W.W. Kartenbeck J. Outer mitochondrial membrane continuous with endoplasmic reticulum.Protoplasma. 1971; 73: 35-41Google Scholar, 29Pickett C.B. Montisano D. Eisner D. Cascarano J. The physical association between rat liver mitochondria and rough endoplasmic reticulum. I. Isolation, electron microscopic examination and sedimentation equilibrium centrifugation analyses of rough endoplasmic reticulum-mitochondrial complexes.Exp. Cell Res. 1980; 128: 343-352Google Scholar). More recent studies have also described these associations both morphologically and biochemically (30Ardail D. Lerme F. Louisot P. Involvement of contact sites in phosphatidylserine import into liver mitochondria.J. Biol. Chem. 1991; 266: 7978-7981Google Scholar, 31Vance J.E. Phospholipid synthesis in a membrane fraction associated with mitochondria.J. Biol. Chem. 1990; 265: 7248-7256Google Scholar, 32Shiao Y.J. Lupo G. Vance J.E. Evidence that phosphatidylserine is imported into mitochondria via a mitochondria-associated membrane and that the majority of phosphatidylethanolamine is derived from decarboxylation of phosphatidylserine.J. Biol. Chem. 1995; 270: 11190-11198Google Scholar, 33Gaigg B. Simbeni R. Hrastnik C. Paltauf F. Daum G. Characterization of a microsomal subfraction associated with mitochondria of the yeast, Saccharomyces cerevisiae. Involvement in synthesis and import of phospholipids into mitochondria.Biochim. Biophys. Acta. 1995; 1234: 214-220Google Scholar, 34Achleitner G. Gaigg B. Krasser A. Kainersdorfer E. Kohlwein S. Perktold A. Zellnig G. Daum G. Association between the endoplasmic reticulum and mitochondria of yeast facilitates interorganelle transport of phospholipids through membrane contact.Eur. J. Biochem. 1999; 264: 545-553Google Scholar). In addition, studies with permeabilized cells provided evidence that PtdSer movement between the ER and mitochondria requires a physical interaction between the organelles that is not easily disrupted (27Voelker D.R. Characterization of phosphatidylserine synthesis and translocation in permeabilized animal cells.J. Biol. Chem. 1990; 265: 14340-14346Google Scholar). Subfractionation of mitochondrial preparations has also revealed the presence of a specialized subpopulation of the ER that is tightly associated with the mitochondrial outer membrane in mammalian cells and yeast (31Vance J.E. Phospholipid synthesis in a membrane fraction associated with mitochondria.J. Biol. Chem. 1990; 265: 7248-7256Google Scholar, 33Gaigg B. Simbeni R. Hrastnik C. Paltauf F. Daum G. Characterization of a microsomal subfraction associated with mitochondria of the yeast, Saccharomyces cerevisiae. Involvement in synthesis and import of phospholipids into mitochondria.Biochim. Biophys. Acta. 1995; 1234: 214-220Google Scholar). The specialized region of the ER is now referred to as the mitochondria-associated membrane, and given the acronym MAM. Strikingly, the MAM fraction is enriched in PtdSer synthase relative to the bulk ER (31Vance J.E. Phospholipid synthesis in a membrane fraction associated with mitochondria.J. Biol. Chem. 1990; 265: 7248-7256Google Scholar, 33Gaigg B. Simbeni R. Hrastnik C. Paltauf F. Daum G. Characterization of a microsomal subfraction associated with mitochondria of the yeast, Saccharomyces cerevisiae. Involvement in synthesis and import of phospholipids into mitochondria.Biochim. Biophys. Acta. 1995; 1234: 214-220Google Scholar). This enrichment in PtdSer synthase might be expected if one function of the MAM is to provide a selected pool of PtdSer to the mitochondria. Additional morphological studies in mammalian cells have also described similar close associations among other organelles including those between Golgi stacks and the ER in three-dimensional reconstructions (35Marsh B.J. Mastronarde D.N. Buttle K.F. Howell K.E. McIntosh J.R. Organellar relationships in the Golgi region of the pancreatic beta cell line, HIT-T15, visualized by high resolution electron tomography.Proc. Natl. Acad. Sci. USA. 2001; 98: 2399-2406Google Scholar). In yeast, a new subpopulation of the ER has recently been described that is closely associated with the plasma membrane (36Pichler H. Gaigg B. Hrastnik C. Achleitner G. Kohlwein S.D. Zellnig G. Perktold A. Daum G. A subfraction of the yeast endoplasmic reticulum associates with the plasma membrane and has a high capacity to synthesize lipids.Eur. J. Biochem. 2001; 268: 2351-2361Google Scholar). This population of the ER has been given the name plasma membrane-associated membrane and is referred to by the acronym PAM. The PAM also shows enrichment in PtdSer synthase relative to the bulk ER pool, and has been proposed as a transfer sight for PtdSer to the cell surface. Currently, we know very little about these zones of contact between different organelle membranes. A number of obvious critical questions about these zones of apposition between organelles need to be addressed including: 1) How are they formed? 2) How are they stabilized? 3) What are their molecular constituents? 4) How are these membrane contacts regulated? 5) If they are sites of lipid transport, are all lipids transferred, or only a select population? 6) Are the lipid transfers all ATP independent? 7) Can the association between the membranes be disrupted by metabolic poisons? 8) Can genetic screens be developed to isolate mutants defective in their formation? One approach to examining interorganelle lipid transport is to exploit the powerful genetic tools available in the yeast Saccharomyces cervisiae. Work in the author’s laboratory has mainly focused on using this approach. An outline of the salient features of the cytogeography of aminoglycerophospholipid synthesis, transport, and metabolism is shown in Fig. 1. In yeast, PtdSer synthesized in the ER is transported to the mitochondria, the Golgi-vacuole, or other organelles. When PtdSer arrives at the mitochondria, it is imported to the inner membrane and decarboxylated by Psd1p to form PtdEtn (37Wu W.I. Voelker D.R. Biochemistry and genetics of interorganelle aminoglycerophospholipid transport.Semin. Cell Dev. Biol. 2002; 13: 185-195Google Scholar). Likewise, when PtdSer arrives at the Golgi-vacuole, it is decarboxylated to form PtdEtn at the locus of Psd2p (37Wu W.I. Voelker D.R. Biochemistry and genetics of interorganelle aminoglycerophospholipid transport.Semin. Cell Dev. Biol. 2002; 13: 185-195Google Scholar). The PtdEtn produced in either the mitochondria or the Golgi-vacuole is exported from these organelles and returned to the ER for methylation by Pem1p and Pem2p to form PtdCho (2Paltauf F. Kohlwein S.D. Henry S.A. Regulation and compartmentalization of lipid synthesis in yeast.in: Jones E.W. Pringle J.R. Broach J.R. The Molecular and Cellular Biology of the Yeast Saccharomyces. Vol. 2. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1992: 415-500Google Scholar). Mammalian cells also possess the pathways for PtdSer transport into the mitochondria and PtdEtn export out of the mitochondria. However, in mammalian cells the methylation of PtdEtn to PtdCho is primarily restricted to liver tissue. Both yeast and mammalian cells can also synthesize PtdEtn and PtdCho in the ER by the Kennedy pathways that originate with cytosolic Etn and Cho (37Wu W.I. Voelker D.R. Biochemistry and genetics of interorganelle aminoglycerophospholipid transport.Semin. Cell Dev. Biol. 2002; 13: 185-195Google Scholar). Null alleles have been constructed for the yeast PtdSer decarboxylases and the strains are denoted psd1Δ and psd2Δ, respectively (38Trotter P.J. Pedretti J. Voelker D.R. Phosphatidylserine decarboxylase from Saccharomyces cerevisiae : isolation of mutants, cloning of the gene and creation of the null phenotype.J. Biol. Chem. 1993; 268: 21416-21424Google Scholar, 39Trotter P.J. Pedretti J. Yates R. Voelker D.R. Phosphatidylserine decarboxylase 2 of Saccharomyces cerevisiae : Cloning and mapping of the gene, heterologous expression and creation of the null allele.J. Biol. Chem. 1995; 270: 6071-6080Google Scholar). The basic genetic strategies employed to isolate potential yeast mutants in lipid traffic fall into two categories. In the first category, psd2Δ strains are used. These strains must rely on either the mitochondrial Psd1p pathway for the synthesis of PtdEtn and PtdCho or the Kennedy pathways present in the ER. The psd2Δ cells are mutagenized and Etn requiring cells (auxotrophs) are selected. The logic of this approach is to create mutations in genes encoding proteins that participate in or regulate PtdSer transport to the mitochondria or PtdEtn export out of the mitochondria. The Kennedy pathway present in the ER allows the PtdEtn and PtdCho needs of the cell to be partially or fully satisfied in the mutants when they are supplemented with Etn (37Wu W.I. Voelker D.R. Biochemistry and genetics of interorganelle aminoglycerophospholipid transport.Semin. Cell Dev. Biol. 2002; 13: 185-195Google Scholar). The second category of mutants is produced from psd1Δ strains. These strains must rely on either the Golgi-vacuole Psd2p pathway for the production of PtdEtn and PtdCho, or the Kennedy pathways present in the ER. These strains are mutagenized to create defects in PtdSer transport to the Golgi-vacuole, or PtdEtn export from these organelles. The cells harboring these transport defects are also identified as Etn auxotrophs. The Etn supplementation under these conditions allows the PtdEtn and PtdCho requirements of the cells to be either fully or partially satisfied. In the original development of the genetic approach to isolate lipid transport mutants in yeast, several simplifying hypotheses were made. One hypothesis assumes that specific gene products regulate lipid traffic to and from the mitochondria and to and from the Golgi-vacuole. At the outset, the pathways for PtdSer transport to the mitochondria and the Golgi-vacuole were named PSTA and PSTB, respectively. In a similar manner, the pathways for PtdEtn export from the mitochondria and the Golgi-vacuole were named PEEA and PEEB, respectively. By convention in yeast nomenclature, genes appear as upper-case italic (PSTA), and mutations in lower-case italic (pstA), and proteins are designated in upper and lower case standard text with a terminal letter p (PstAp). Thus far we have identified mutations and genes affecting the PSTA and PSTB pathways. A second hypothesis generated in the genetic approach was that PtdEtn and PtdCho produced by the Kennedy pathways would be sufficient to rescue defects in phospholipid transport along the PSTA and PSTB pathways. The results of genetic screening indicate that the assumptions of this second hypothesis are only partially true. In general the mutants we isolated only have partial defects in lipid transport, but usually strong growth phenotypes. We interpret this to mean that the functioning Kennedy pathways are adequate to rescue mutants that are relatively “leaky” (i.e., allow some reduced level of transport to occur) but are insufficient to compensate for mutants completely arrested in lipid transport. In addition, several genes implicated in lipid transport also appear to be involved in other cellular functions. Work with some of these mutants is described below and now provides new insights into the mechanisms regulating the interorganelle transport of PtdSer. A summary of mutant strains, complementing genes, and gene product functions is given in Table 1.TABLE 1Summary of mutations/genes involved in interorganelle transport of glycerophospholipidsPathwayMutationGeneProtein FunctionRole in TransportPSTApstA1MET30SCF-Ubiquitin ligaseRegulates MAM-to-mitochondria transport of PtdSerCHO-R41UnknownUnknownRegulates outer-to-inner membrane transport of PtdSerPSTBpstB1STT4PtdIns-4-kinaseRegulates PtdSer transport to Psd2ppstB2PSTB2/PDR17/SFH4PtdIns transfer-binding proteinRequired on acceptor membrane for PtdSer transport to Psd2ppsd2-C2ΔPSD2PtdSer decarboxylaseC2 domain is essential for PtdSer transport in vivoMAM, mitochondria-associated membrane; PtdIns, phosphatidylinositol; PtdSer, phosphatidylserine." @default.
• W2100021650 created "2016-06-24" @default.
• W2100021650 creator A5044700206 @default.
• W2100021650 date "2003-03-01" @default.
• W2100021650 modified "2023-10-17" @default.
• W2100021650 title "New perspectives on the regulation of intermembrane glycerophospholipid traffic" @default.
• W2100021650 cites W1503647217 @default.
• W2100021650 cites W1509952659 @default.
• W2100021650 cites W1519919607 @default.
• W2100021650 cites W1532455251 @default.
• W2100021650 cites W1545007954 @default.
• W2100021650 cites W1563266905 @default.
• W2100021650 cites W1565474821 @default.
• W2100021650 cites W1568987948 @default.
• W2100021650 cites W1575864823 @default.
• W2100021650 cites W1586395651 @default.
• W2100021650 cites W1587977582 @default.
• W2100021650 cites W1588347494 @default.
• W2100021650 cites W1595781572 @default.
• W2100021650 cites W1675439761 @default.
• W2100021650 cites W1695245462 @default.
• W2100021650 cites W1964727206 @default.
• W2100021650 cites W1967042190 @default.
• W2100021650 cites W1969066518 @default.
• W2100021650 cites W1971050831 @default.
• W2100021650 cites W1973900880 @default.
• W2100021650 cites W1985225337 @default.
• W2100021650 cites W1986656228 @default.
• W2100021650 cites W1988984887 @default.
• W2100021650 cites W1990662798 @default.
• W2100021650 cites W1990690757 @default.
• W2100021650 cites W1990826643 @default.
• W2100021650 cites W1994025530 @default.
• W2100021650 cites W1996477510 @default.
• W2100021650 cites W2001901220 @default.
• W2100021650 cites W2003669697 @default.
• W2100021650 cites W2005593816 @default.
• W2100021650 cites W2016459483 @default.
• W2100021650 cites W2020955297 @default.
• W2100021650 cites W2024169922 @default.
• W2100021650 cites W2039885650 @default.
• W2100021650 cites W2039932572 @default.
• W2100021650 cites W2041525134 @default.
• W2100021650 cites W2051025707 @default.
• W2100021650 cites W2053914845 @default.
• W2100021650 cites W2064731387 @default.
• W2100021650 cites W2067776100 @default.
• W2100021650 cites W2069512939 @default.
• W2100021650 cites W2070022566 @default.
• W2100021650 cites W2071967767 @default.
• W2100021650 cites W2075205928 @default.
• W2100021650 cites W2080273350 @default.
• W2100021650 cites W2081681270 @default.
• W2100021650 cites W2083065274 @default.
• W2100021650 cites W2086636140 @default.
• W2100021650 cites W2091589417 @default.
• W2100021650 cites W2092562744 @default.
• W2100021650 cites W2095374461 @default.
• W2100021650 cites W2096881442 @default.
• W2100021650 cites W2098329073 @default.
• W2100021650 cites W2105277532 @default.
• W2100021650 cites W2112727465 @default.
• W2100021650 cites W2115909676 @default.
• W2100021650 cites W2133488326 @default.
• W2100021650 cites W2136816588 @default.
• W2100021650 cites W2141189073 @default.
• W2100021650 cites W2152528438 @default.
• W2100021650 cites W2152561526 @default.
• W2100021650 cites W2161708108 @default.
• W2100021650 cites W2164186679 @default.
• W2100021650 cites W2170634115 @default.
• W2100021650 cites W2336496644 @default.
• W2100021650 cites W3103055356 @default.
• W2100021650 cites W4230766242 @default.
• W2100021650 cites W4231733340 @default.
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