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Phosphatidic Acid Plays a Central Role in the Transcriptional Regulation of Glycerophospholipid Synthesis in Saccharomyces cerevisiae

2007; Elsevier BV; Volume: 282; Issue: 52 Linguagem: Inglês

10.1074/jbc.r700038200

ISSN

1083-351X

Autores

George Carman, Susan A. Henry,

Tópico(s)

Cellular transport and secretion

Resumo

In eukaryotic cells, PA 2The abbreviations used are: PAphosphatidic acidDAGdiacylglycerolTAGtriacylglycerolPCphosphatidylcholinePIphosphatidylinositolPEphosphatidylethanolaminePSphosphatidylserineUASINOupstream activating sequence inositol-responsive elementERendoplasmic reticulum is a central precursor for the synthesis of major glycerophospholipids, DAG and TAG, as well as a major signaling lipid. In mammalian cells, PA is implicated as an activator of cell growth and proliferation, vesicular trafficking, secretion, and endocytosis (1Waggoner D.W. Xu J. Singh I. Jasinska R. Zhang Q.X. Brindley D.N. Biochim. Biophys. Acta. 1999; 1439: 299-316Crossref PubMed Scopus (114) Google Scholar, 2Sciorra V.A. Morris A.J. Biochim. Biophys. Acta. 2002; 1582: 45-51Crossref PubMed Scopus (145) Google Scholar, 3Testerink C. Munnik T. Trends Plant Sci. 2005; 10: 368-375Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, 4Wang X. Devaiah S.P. Zhang W. Welti R. Prog. Lipid Res. 2006; 45: 250-278Crossref PubMed Scopus (577) Google Scholar, 5Brindley D.N. J. Cell. Biochem. 2004; 92: 900-912Crossref PubMed Scopus (185) Google Scholar, 6Howe A.G. McMaster C.R. Can. J. Physiol. Pharmacol. 2006; 84: 29-38Crossref PubMed Google Scholar, 7Foster D.A. Cancer Res. 2007; 67: 1-4Crossref PubMed Scopus (139) Google Scholar). In plants, PA is implicated in seed germination and response to stress induced by drought, salinity, and low temperature (3Testerink C. Munnik T. Trends Plant Sci. 2005; 10: 368-375Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, 4Wang X. Devaiah S.P. Zhang W. Welti R. Prog. Lipid Res. 2006; 45: 250-278Crossref PubMed Scopus (577) Google Scholar). phosphatidic acid diacylglycerol triacylglycerol phosphatidylcholine phosphatidylinositol phosphatidylethanolamine phosphatidylserine upstream activating sequence inositol-responsive element endoplasmic reticulum The signaling roles of PA in the yeast Saccharomyces cerevisiae have not received as much attention as they have in higher eukaryotic cells. However, it is known that PA production via phospholipase D-mediated turnover of PC is necessary for suppression of growth and membrane trafficking defects in mutants defective in Sec14p, an essential PI/PC-binding protein (8Patton-Vogt J.L. Griac P. Sreenivas A. Bruno V. Dowd S. Swede M.J. Henry S.A. J. Biol. Chem. 1997; 272: 20873-20883Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 9Sreenivas A. Patton-Vogt J.L. Bruno V. Griac P. Henry S.A. J. Biol. Chem. 1998; 273: 16635-16638Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 10Xie Z.G. Fang M. Rivas M.P. Faulkner A.J. Sternweis P.C. Engebrecht J. Bankaitis V.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 12346-12351Crossref PubMed Scopus (145) Google Scholar). In addition, PA production via phospholipase D is implicated in Spo20p-mediated fusion of vesicles with the prespore membrane during sporogenesis (11Rudge S.A. Sciorra V.A. Iwamoto M. Zhou C. Strahl T. Morris A.J. Thorner J. Engebrecht J. Mol. Biol. Cell. 2004; 15: 207-218Crossref PubMed Scopus (52) Google Scholar, 12Nakanishi H. Morishita M. Schwartz C.L. Coluccio A. Engebrecht J. Neiman A.M. J. Cell Sci. 2006; 119: 1406-1415Crossref PubMed Scopus (90) Google Scholar). The best studied regulatory function of PA in S. cerevisiae is its role as a signaling molecule in the transcriptional regulation of glycerophospholipid synthesis itself, the major topic of this review. We will focus on the pathways generating and utilizing PA in yeast and the evidence that PA plays a central role in the transcriptional regulation of glycerophospholipid synthesis. PA is the precursor of all membrane glycerophospholipids and the storage lipid TAG in S. cerevisiae (Fig. 1) (13Rattray J.B. Schibeci A. Kidby D.K. Bacteriol. Rev. 1975; 39: 197-231Crossref PubMed Google Scholar, 14Henry S.A. Strathern J.N. Jones E.W. Broach J.R. The Molecular Biology of the Yeast Saccharomyces: Metabolism and Gene Expression. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1982: 101-158Google Scholar, 15Paltauf F. Kohlwein S.D. Henry S.A. Jones E.W. Pringle J.R. Broach J.R. The Molecular and Cellular Biology of the Yeast Saccharomyces: Gene Expression. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1992: 415-500Google Scholar, 16Czabany T. Athenstaedt K. Daum G. Biochim. Biophys. Acta. 2007; 1771: 299-309Crossref PubMed Scopus (185) Google Scholar). In the de novo pathway, PA is synthesized from glycerol 3-phosphate and then used for the synthesis of glycerophospholipids via the liponucleotide intermediate CDP-DAG (i.e. CDP-DAG pathway) (Fig. 1). PA is also used for the synthesis of PE and PC via DAG in the Kennedy pathway (CDP-ethanolamine and CDP-choline branches, respectively) (Fig. 1). The DAG derived from PA is also used for the synthesis of TAG (Fig. 1). Cells grown in the absence of choline synthesize PC primarily via the CDP-DAG pathway (17McMaster C.R. Bell R.M. J. Biol. Chem. 1994; 269: 14776-14783Abstract Full Text PDF PubMed Google Scholar). In contrast, cells supplemented with choline synthesize PC primarily via the Kennedy pathway (17McMaster C.R. Bell R.M. J. Biol. Chem. 1994; 269: 14776-14783Abstract Full Text PDF PubMed Google Scholar). Nonetheless, PC is synthesized from PA by both the CDP-DAG and Kennedy pathways regardless of whether choline is added to the growth medium (8Patton-Vogt J.L. Griac P. Sreenivas A. Bruno V. Dowd S. Swede M.J. Henry S.A. J. Biol. Chem. 1997; 272: 20873-20883Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 18Morash S.C. McMaster C.R. Hjelmstad R.H. Bell R.M. J. Biol. Chem. 1994; 269: 28769-28776Abstract Full Text PDF PubMed Google Scholar, 19McGee T.P. Skinner H.B. Whitters E.A. Henry S.A. Bankaitis V.A. J. Cell Biol. 1994; 124: 273-287Crossref PubMed Scopus (152) Google Scholar, 20McMaster C.R. Bell R.M. J. Biol. Chem. 1994; 269: 28010-28016Abstract Full Text PDF PubMed Google Scholar, 21Ostrander D.B. O'Brien D.J. Gorman J.A. Carman G.M. J. Biol. Chem. 1998; 273: 18992-19001Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 22Kim K.-H. Voelker D.R. Flocco M.T. Carman G.M. J. Biol. Chem. 1998; 273: 6844-6852Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). The choline required is derived from the phospholipase D-mediated turnover of the PC synthesized via the CDP-DAG pathway (Fig. 1) (8Patton-Vogt J.L. Griac P. Sreenivas A. Bruno V. Dowd S. Swede M.J. Henry S.A. J. Biol. Chem. 1997; 272: 20873-20883Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 10Xie Z.G. Fang M. Rivas M.P. Faulkner A.J. Sternweis P.C. Engebrecht J. Bankaitis V.A. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 12346-12351Crossref PubMed Scopus (145) Google Scholar). The PA produced is reincorporated into glycerophospholipids (8Patton-Vogt J.L. Griac P. Sreenivas A. Bruno V. Dowd S. Swede M.J. Henry S.A. J. Biol. Chem. 1997; 272: 20873-20883Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Mutants defective in PC synthesis via the CDP-DAG pathway require choline for growth; they synthesize PC via the CDP-choline branch of the Kennedy pathway (23Atkinson K. Fogel S. Henry S.A. J. Biol. Chem. 1980; 255: 6653-6661Abstract Full Text PDF PubMed Google Scholar, 24Atkinson K.D. Jensen B. Kolat A.I. Storm E.M. Henry S.A. Fogel S. J. Bacteriol. 1980; 141: 558-564Crossref PubMed Google Scholar, 25Trotter P.J. Voelker D.R. J. Biol. Chem. 1995; 270: 6062-6070Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 26Trotter P.J. Pedretti J. Yates R. Voelker D.R. J. Biol. Chem. 1995; 270: 6071-6080Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 27Kodaki T. Yamashita S. J. Biol. Chem. 1987; 262: 15428-15435Abstract Full Text PDF PubMed Google Scholar, 28Kodaki T. Yamashita S. Eur. J. Biochem. 1989; 185: 243-251Crossref PubMed Scopus (88) Google Scholar, 29Summers E.F. Letts V.A. McGraw P. Henry S.A. Genetics. 1988; 120: 909-922Crossref PubMed Google Scholar, 30McGraw P. Henry S.A. Genetics. 1989; 122: 317-330Crossref PubMed Google Scholar). Mutants defective in the synthesis of PS (23Atkinson K. Fogel S. Henry S.A. J. Biol. Chem. 1980; 255: 6653-6661Abstract Full Text PDF PubMed Google Scholar, 24Atkinson K.D. Jensen B. Kolat A.I. Storm E.M. Henry S.A. Fogel S. J. Bacteriol. 1980; 141: 558-564Crossref PubMed Google Scholar) and PE (25Trotter P.J. Voelker D.R. J. Biol. Chem. 1995; 270: 6062-6070Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 26Trotter P.J. Pedretti J. Yates R. Voelker D.R. J. Biol. Chem. 1995; 270: 6071-6080Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar) can synthesize PC if they are supplemented with ethanolamine. The ethanolamine is used to synthesize PE via the CDP-ethanolamine branch of the Kennedy pathway, which is then methylated to form PC in the CDP-DAG pathway (Fig. 1) (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar). Kennedy pathway mutants (e.g. cki1 eki1 and cpt1 ept1) defective in both the CDP-choline and CDP-ethanolamine branches must synthesize PC via the CDP-DAG pathway (18Morash S.C. McMaster C.R. Hjelmstad R.H. Bell R.M. J. Biol. Chem. 1994; 269: 28769-28776Abstract Full Text PDF PubMed Google Scholar, 20McMaster C.R. Bell R.M. J. Biol. Chem. 1994; 269: 28010-28016Abstract Full Text PDF PubMed Google Scholar, 33Kim K. Kim K.-H. Storey M.K. Voelker D.R. Carman G.M. J. Biol. Chem. 1999; 274: 14857-14866Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). However, unlike mutants defective in the CDP-DAG pathway (23Atkinson K. Fogel S. Henry S.A. J. Biol. Chem. 1980; 255: 6653-6661Abstract Full Text PDF PubMed Google Scholar, 24Atkinson K.D. Jensen B. Kolat A.I. Storm E.M. Henry S.A. Fogel S. J. Bacteriol. 1980; 141: 558-564Crossref PubMed Google Scholar, 25Trotter P.J. Voelker D.R. J. Biol. Chem. 1995; 270: 6062-6070Abstract Full Text Full Text PDF PubMed Scopus (204) Google Scholar, 26Trotter P.J. Pedretti J. Yates R. Voelker D.R. J. Biol. Chem. 1995; 270: 6071-6080Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 27Kodaki T. Yamashita S. J. Biol. Chem. 1987; 262: 15428-15435Abstract Full Text PDF PubMed Google Scholar, 28Kodaki T. Yamashita S. Eur. J. Biochem. 1989; 185: 243-251Crossref PubMed Scopus (88) Google Scholar, 29Summers E.F. Letts V.A. McGraw P. Henry S.A. Genetics. 1988; 120: 909-922Crossref PubMed Google Scholar, 30McGraw P. Henry S.A. Genetics. 1989; 122: 317-330Crossref PubMed Google Scholar), Kennedy pathway mutants do not exhibit any auxotrophic requirements (18Morash S.C. McMaster C.R. Hjelmstad R.H. Bell R.M. J. Biol. Chem. 1994; 269: 28769-28776Abstract Full Text PDF PubMed Google Scholar, 33Kim K. Kim K.-H. Storey M.K. Voelker D.R. Carman G.M. J. Biol. Chem. 1999; 274: 14857-14866Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). The synthesis of PC is coordinately regulated with the synthesis of PI (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar, 34Gaspar M.L. Aregullin M.A. Jesch S.A. Nunez L.R. Villa-Garcia M. Henry S.A. Biochim. Biophys. Acta. 2007; 1771: 241-254Crossref PubMed Scopus (60) Google Scholar, 35Carman G.M. Han G.-S. Biochim. Biophys. Acta. 2007; 1771: 322-330Crossref PubMed Scopus (49) Google Scholar). This regulation is mediated by genetic and biochemical mechanisms (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar, 34Gaspar M.L. Aregullin M.A. Jesch S.A. Nunez L.R. Villa-Garcia M. Henry S.A. Biochim. Biophys. Acta. 2007; 1771: 241-254Crossref PubMed Scopus (60) Google Scholar, 35Carman G.M. Han G.-S. Biochim. Biophys. Acta. 2007; 1771: 322-330Crossref PubMed Scopus (49) Google Scholar, 36Carman G.M. Zeimetz G.M. J. Biol. Chem. 1996; 271: 13293-13296Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar, 37Carman G.M. Kersting M.C. Biochem. Cell Biol. 2004; 82: 62-70Crossref PubMed Scopus (44) Google Scholar). In this review, we will focus on the transcriptional regulation of glycerophospholipid synthesis gene expression. Several glycerophospholipid synthesis genes are maximally expressed when inositol is absent from the growth medium and repressed when inositol is added to the growth medium. The repression by inositol requires PC synthesis and is enhanced by the inclusion of choline in the growth medium (15Paltauf F. Kohlwein S.D. Henry S.A. Jones E.W. Pringle J.R. Broach J.R. The Molecular and Cellular Biology of the Yeast Saccharomyces: Gene Expression. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1992: 415-500Google Scholar, 31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar, 38Carman G.M. Henry S.A. Annu. Rev. Biochem. 1989; 58: 635-669Crossref PubMed Google Scholar, 39Greenberg M.L. Lopes J.M. Microbiol. Rev. 1996; 60: 1-20Crossref PubMed Google Scholar). The expression of glycerophospholipid synthesis genes is also repressed when cells enter the stationary phase of growth and when cells are depleted of nitrogen or zinc (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar, 35Carman G.M. Han G.-S. Biochim. Biophys. Acta. 2007; 1771: 322-330Crossref PubMed Scopus (49) Google Scholar). The repression in the stationary phase and by nitrogen and zinc depletion occurs in the absence of inositol (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar, 35Carman G.M. Han G.-S. Biochim. Biophys. Acta. 2007; 1771: 322-330Crossref PubMed Scopus (49) Google Scholar, 40Griac P. Henry S.A. Nucleic Acids Res. 1999; 27: 2043-2050Crossref PubMed Scopus (19) Google Scholar). The coordinate regulation of the glycerophospholipid synthesis genes by inositol supplementation, growth phase, and nutrient depletion is dependent on the transcriptional regulatory proteins Ino2p (41Nikoloff D.M. McGraw P. Henry S.A. Nucleic Acids Res. 1992; 20: 3253Crossref PubMed Scopus (78) Google Scholar), Ino4p (42Hoshizaki D.K. Hill J.E. Henry S.A. J. Biol. Chem. 1990; 265: 4736-4745Abstract Full Text PDF PubMed Google Scholar), and Opi1p (43White M.J. Hirsch J.P. Henry S.A. J. Biol. Chem. 1991; 266: 863-872Abstract Full Text PDF PubMed Google Scholar), as well as a UASINO cis-acting element (44Kodaki T. Nikawa J. Hosaka K. Yamashita S. J. Bacteriol. 1991; 173: 7992-7995Crossref PubMed Google Scholar, 45Lopes J.M. Hirsch J.P. Chorgo P.A. Schulze K.L. Henry S.A. Nucleic Acids Res. 1991; 19: 1687-1693Crossref PubMed Scopus (100) Google Scholar, 46Schuller H.J. Hahn A. Troster F. Schutz A. Schweizer E. EMBO J. 1992; 11: 107-114Crossref PubMed Scopus (104) Google Scholar, 47Schuller H.J. Richter K. Hoffmann B. Ebbert R. Schweizer E. FEBS Lett. 1995; 370: 149-152Crossref PubMed Scopus (55) Google Scholar) present in the promoters of the glycerophospholipid synthesis genes (Fig. 2) (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar, 39Greenberg M.L. Lopes J.M. Microbiol. Rev. 1996; 60: 1-20Crossref PubMed Google Scholar, 48Ambroziak J. Henry S.A. J. Biol. Chem. 1994; 269: 15344-15349Abstract Full Text PDF PubMed Google Scholar). The UASINO element contains a consensus binding site (CATGTGAAAT) for an Ino2p-Ino4p heterodimer complex that activates the expression of glycerophospholipid synthesis genes (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar, 39Greenberg M.L. Lopes J.M. Microbiol. Rev. 1996; 60: 1-20Crossref PubMed Google Scholar, 49Hirsch J.P. Henry S.A. Mol. Cell. Biol. 1986; 6: 3320-3328Crossref PubMed Scopus (181) Google Scholar, 50Bachhawat N. Ouyang Q. Henry S.A. J. Biol. Chem. 1995; 270: 25087-25095Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 51Loewy B.S. Henry S.A. Mol. Cell. Biol. 1984; 4: 2479-2485Crossref PubMed Scopus (58) Google Scholar, 52Schwank S. Ebbert R. Rautenstrauss K. Schweizer E. Schuller H.J. Nucleic Acids Res. 1995; 23: 230-237Crossref PubMed Scopus (109) Google Scholar). Repression of these genes is dependent on Opi1p (43White M.J. Hirsch J.P. Henry S.A. J. Biol. Chem. 1991; 266: 863-872Abstract Full Text PDF PubMed Google Scholar, 53Greenberg M. Reiner B. Henry S.A. Genetics. 1982; 100: 19-33Crossref PubMed Google Scholar), which inhibits transcriptional activation of the Ino2p-Ino4p complex by binding to Ino2p (Fig. 2) (54Wagner C. Dietz M. Wittmann J. Albrecht A. Schuller H.J. Mol. Microbiol. 2001; 41: 155-166Crossref PubMed Scopus (85) Google Scholar). In fact, ino2 and ino4 mutants exhibit constitutively repressed levels of UASINO-containing genes, whereas opi1 mutants exhibit constitutively derepressed levels of UASINO-containing genes (15Paltauf F. Kohlwein S.D. Henry S.A. Jones E.W. Pringle J.R. Broach J.R. The Molecular and Cellular Biology of the Yeast Saccharomyces: Gene Expression. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1992: 415-500Google Scholar, 31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 38Carman G.M. Henry S.A. Annu. Rev. Biochem. 1989; 58: 635-669Crossref PubMed Google Scholar, 39Greenberg M.L. Lopes J.M. Microbiol. Rev. 1996; 60: 1-20Crossref PubMed Google Scholar). Because of the misregulation of INO1 expression, ino2 and ino4 mutants are auxotrophic for inositol, whereas opi1 mutants produce excessive amounts of inositol and excrete it into the growth medium (15Paltauf F. Kohlwein S.D. Henry S.A. Jones E.W. Pringle J.R. Broach J.R. The Molecular and Cellular Biology of the Yeast Saccharomyces: Gene Expression. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1992: 415-500Google Scholar, 31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 38Carman G.M. Henry S.A. Annu. Rev. Biochem. 1989; 58: 635-669Crossref PubMed Google Scholar, 39Greenberg M.L. Lopes J.M. Microbiol. Rev. 1996; 60: 1-20Crossref PubMed Google Scholar). Thus, inositol auxotrophy and inositol excretion are used as indicators of the misregulation of INO1 and other UASINO-containing genes (15Paltauf F. Kohlwein S.D. Henry S.A. Jones E.W. Pringle J.R. Broach J.R. The Molecular and Cellular Biology of the Yeast Saccharomyces: Gene Expression. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY1992: 415-500Google Scholar, 31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 38Carman G.M. Henry S.A. Annu. Rev. Biochem. 1989; 58: 635-669Crossref PubMed Google Scholar, 39Greenberg M.L. Lopes J.M. Microbiol. Rev. 1996; 60: 1-20Crossref PubMed Google Scholar). Recent genome-wide studies using microarray analysis have revealed the full extent of genes responsive to addition of inositol and choline to the growth medium and dependent for this regulation on Ino2p, Ino4p, and Opi1p (55Santiago T.C. Mamoun C.B. J. Biol. Chem. 2003; 278: 38723-38730Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 56Jesch S.A. Zhao X. Wells M.T. Henry S.A. J. Biol. Chem. 2005; 280: 9106-9118Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 57Jesch S.A. Liu P. Zhao X. Wells M.T. Henry S.A. J. Biol. Chem. 2006; 281: 24070-24083Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). These studies also revealed several other major classes of genes in addition to and independent of Ino2p, Ino4p, and Opi1p that respond to signals arising in the ER following inositol addition that are potentially related to lipid metabolism (57Jesch S.A. Liu P. Zhao X. Wells M.T. Henry S.A. J. Biol. Chem. 2006; 281: 24070-24083Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Mutations that block the utilization of PA for PC synthesis cause the derepression of INO1 and other UASINO-containing genes, whereas mutations that increase the utilization of PA cause the repression of UASINO-containing genes (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar). Mutants defective in the structural genes leading to PC from PA via the CDP-DAG pathway (Fig. 1) share in common the inositol excretion phenotype (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 39Greenberg M.L. Lopes J.M. Microbiol. Rev. 1996; 60: 1-20Crossref PubMed Google Scholar). As indicated above, the inositol excretion phenotype results from the loss of Opi1p repressor function, which leads to the constitutive derepression and overexpression of INO1. Moreover, the remaining wild-type genes in a particular CDP-DAG pathway mutant cannot be repressed by inositol supplementation (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar). The inositol excretion phenotype of the CDP-DAG pathway mutants beginning with the formation of PS from CDP-DAG can be complemented if the mutants are supplemented with a water-soluble precursor that allows for the synthesis of glycerophospholipids via the Kennedy pathway (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar). The supplementation of the Kennedy pathway precursor also permits the inositol-mediated repression of the remaining wild-type genes in a particular CDP-DAG pathway mutant (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar). A complete block of the first step in the CDP-DAG pathway (e.g. cds1) is lethal (58Shen H. Heacock P.N. Clancey C.J. Dowhan W. J. Biol. Chem. 1996; 271: 789-795Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). However, partial (59Klig L.S. Homann M.J. Kohlwein S.D. Kelley M.J. Henry S.A. Carman G.M. J. Bacteriol. 1988; 170: 1878-1886Crossref PubMed Google Scholar) or conditional (60Shen H. Dowhan W. J. Biol. Chem. 1996; 271: 29043-29048Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar) cds1 alleles derepress INO1 and excrete inositol (60Shen H. Dowhan W. J. Biol. Chem. 1996; 271: 29043-29048Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). The inositol excretion phenotype of the cds1 mutants cannot be overcome by supplementation with a Kennedy pathway precursor, nor will inositol mediate the repression of other UASINO-containing genes in these strains (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar, 32Carman G.M. Henry S.A. Prog. Lipid Res. 1999; 38: 361-399Crossref PubMed Scopus (264) Google Scholar, 59Klig L.S. Homann M.J. Kohlwein S.D. Kelley M.J. Henry S.A. Carman G.M. J. Bacteriol. 1988; 170: 1878-1886Crossref PubMed Google Scholar). Thus, mutants defective at every step in the synthesis of PS, PE, and PC from CDP-DAG exhibit increases in PA levels and altered regulation of INO1 and have the inositol excretion phenotype. These observations led to the hypothesis that PA is the metabolic signal for INO1 derepression (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar). In contrast, mutants defective in PC synthesis via the CDP-choline branch of the Kennedy pathway do not excrete inositol and exhibit normal regulation of INO1 (61Griac P. Swede M.J. Henry S.A. J. Biol. Chem. 1996; 271: 25692-25698Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar). The Kennedy pathway mutants do, however, exhibit a choline excretion phenotype (8Patton-Vogt J.L. Griac P. Sreenivas A. Bruno V. Dowd S. Swede M.J. Henry S.A. J. Biol. Chem. 1997; 272: 20873-20883Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). Interestingly, Kennedy pathway mutants that also possess a mutation in the SEC14 gene (e.g. cki1 sec14, pct1 sec14, and cpt1 sec14) exhibit extreme choline excretion in combination with an inositol excretion phenotype (8Patton-Vogt J.L. Griac P. Sreenivas A. Bruno V. Dowd S. Swede M.J. Henry S.A. J. Biol. Chem. 1997; 272: 20873-20883Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 9Sreenivas A. Patton-Vogt J.L. Bruno V. Griac P. Henry S.A. J. Biol. Chem. 1998; 273: 16635-16638Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). The excretion of choline and inositol by these double mutants is dependent on the phospholipase D-mediated turnover of PC (8Patton-Vogt J.L. Griac P. Sreenivas A. Bruno V. Dowd S. Swede M.J. Henry S.A. J. Biol. Chem. 1997; 272: 20873-20883Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 9Sreenivas A. Patton-Vogt J.L. Bruno V. Griac P. Henry S.A. J. Biol. Chem. 1998; 273: 16635-16638Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). The finding that excess PA produced by this reaction causes INO1 derepression even in the presence of inositol (8Patton-Vogt J.L. Griac P. Sreenivas A. Bruno V. Dowd S. Swede M.J. Henry S.A. J. Biol. Chem. 1997; 272: 20873-20883Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 9Sreenivas A. Patton-Vogt J.L. Bruno V. Griac P. Henry S.A. J. Biol. Chem. 1998; 273: 16635-16638Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar) further supports the hypothesis that PA provides the signal for derepression of UASINO-containing genes (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar). The enzyme responsible for generating the DAG for glycerophospholipid synthesis via the Kennedy pathway is the PAH1-encoded Mg2+-dependent PA phosphatase (62Han G.-S. Wu W.-I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar). Mutations that affect the activity of this enzyme cause the misregulation of UASINO-containing genes (62Han G.-S. Wu W.-I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar, 63Santos-Rosa H. Leung J. Grimsey N. Peak-Chew S. Siniossoglou S. EMBO J. 2005; 24: 1931-1941Crossref PubMed Scopus (290) Google Scholar, 64O'Hara L. Han G.-S. Peak-Chew S. Grimsey N. Carman G.M. Siniossoglou S. J. Biol. Chem. 2006; 281: 34537-34548Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). A pah1 mutant with reduced activity exhibits derepressed levels of INO1, OPI3, and INO2 (62Han G.-S. Wu W.-I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar, 63Santos-Rosa H. Leung J. Grimsey N. Peak-Chew S. Siniossoglou S. EMBO J. 2005; 24: 1931-1941Crossref PubMed Scopus (290) Google Scholar). However, the level of INO1 derepression is not sufficient to cause inositol excretion (62Han G.-S. Wu W.-I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar, 63Santos-Rosa H. Leung J. Grimsey N. Peak-Chew S. Siniossoglou S. EMBO J. 2005; 24: 1931-1941Crossref PubMed Scopus (290) Google Scholar). This may be the consequence of the significant amount of Mg2+-dependent PA phosphatase activity that remains in pah1 mutant cells (62Han G.-S. Wu W.-I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar). Pah1p is phosphorylated by cyclin-dependent Cdc28p kinase and dephosphorylated by the Nem1p-Spo7p phosphatase complex (63Santos-Rosa H. Leung J. Grimsey N. Peak-Chew S. Siniossoglou S. EMBO J. 2005; 24: 1931-1941Crossref PubMed Scopus (290) Google Scholar). Reduction in Pah1p phosphorylation elevates Mg2+-dependent PA phosphatase activity (64O'Hara L. Han G.-S. Peak-Chew S. Grimsey N. Carman G.M. Siniossoglou S. J. Biol. Chem. 2006; 281: 34537-34548Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar), indicating that phosphorylation inhibits activity. Cells that overexpress a phosphorylation-deficient enzyme are repressed for INO1 and OPI3 and require inositol for growth (64O'Hara L. Han G.-S. Peak-Chew S. Grimsey N. Carman G.M. Siniossoglou S. J. Biol. Chem. 2006; 281: 34537-34548Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). The fact that the inositol auxotrophy of cells overexpressing Mg2+-dependent PA phosphatase activity can be suppressed by an opi1 mutation (64O'Hara L. Han G.-S. Peak-Chew S. Grimsey N. Carman G.M. Siniossoglou S. J. Biol. Chem. 2006; 281: 34537-34548Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar) indicates the role of Opi1p in this regulation. Loewen et al. (65Loewen C.J.R. Roy A. Levine T.P. EMBO J. 2003; 22: 2025-2035Crossref PubMed Scopus (443) Google Scholar, 66Loewen C.J.R. Gaspar M.L. Jesch S.A. Delon C. Ktistakis N.T. Henry S.A. Levine T.P. Science. 2004; 304: 1644-1647Crossref PubMed Scopus (369) Google Scholar, 67Loewen C.J.R. Levine T.P. J. Biol. Chem. 2005; 280: 14097-14104Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar) have shown that the Opi1p repressor, a protein lacking membrane-spanning domains (43White M.J. Hirsch J.P. Henry S.A. J. Biol. Chem. 1991; 266: 863-872Abstract Full Text PDF PubMed Google Scholar), is found at the nuclear/ER membrane and within the nucleus. Opi1p associates with the nuclear/ER membrane through interaction with the integral membrane protein Scs2p (Fig. 2) (65Loewen C.J.R. Roy A. Levine T.P. EMBO J. 2003; 22: 2025-2035Crossref PubMed Scopus (443) Google Scholar). A connection between Scs2p and the regulation of glycerophospholipid synthesis is evident because scs2 mutants are auxotrophic for inositol due to the constitutive repression of INO1 (68Nikawa J. Murakami A. Esumi E. Hosaka K. J. Biochem. (Tokyo). 1995; 118: 39-45Crossref PubMed Scopus (45) Google Scholar, 69Kagiwada S. Hosaka K. Murata M. Nikawa J. Takatsuki A. J. Bacteriol. 1998; 180: 1700-1708Crossref PubMed Google Scholar, 70Kagiwada S. Zen R. J. Biochem. (Tokyo). 2003; 133: 515-522Crossref PubMed Scopus (35) Google Scholar). Thus, attenuation of the repressor activity of Opi1p depends on its association with the nuclear/ER membrane through interaction with Scs2p. Interestingly, the scs2 mutation also results in an increase in PC synthesis via the Kennedy pathway, and a block in the Kennedy pathway (e.g. cki1 scs2) restores normal INO1 expression (70Kagiwada S. Zen R. J. Biochem. (Tokyo). 2003; 133: 515-522Crossref PubMed Scopus (35) Google Scholar). As discussed above, PC synthesis via the Kennedy pathway consumes PA via DAG, and a block in the Kennedy pathway should accumulate PA, thus potentially explaining the suppression of the inositol auxotrophy of scs2 mutants. Although this scenario has not been fully explored experimentally, it is consistent with the notion that PA plays a role in the regulation of INO1 and other UASINO-containing genes. A major breakthrough in our understanding of glycerophospholipid synthesis regulation was the discovery that Opi1p is a PA-binding protein and that its association with the nuclear/ER membrane is stabilized by PA (66Loewen C.J.R. Gaspar M.L. Jesch S.A. Delon C. Ktistakis N.T. Henry S.A. Levine T.P. Science. 2004; 304: 1644-1647Crossref PubMed Scopus (369) Google Scholar). Moreover, Loewen et al. (66Loewen C.J.R. Gaspar M.L. Jesch S.A. Delon C. Ktistakis N.T. Henry S.A. Levine T.P. Science. 2004; 304: 1644-1647Crossref PubMed Scopus (369) Google Scholar) have shown that Opi1p translocates from the nuclear/ER membrane into the nucleus upon inositol supplementation, which results in a reduction in the level of PA coincident with its use as a precursor in the synthesis of PI via CDP-DAG (Fig. 2). The translocation of Opi1p in response to inositol supplementation coincides with the repression of INO1 expression (66Loewen C.J.R. Gaspar M.L. Jesch S.A. Delon C. Ktistakis N.T. Henry S.A. Levine T.P. Science. 2004; 304: 1644-1647Crossref PubMed Scopus (369) Google Scholar). Thus, a key regulatory switch for controlling the expression of INO1 and other UASINO-containing genes is the localization of Opi1p, which is dependent on the presence of a certain amount of PA that is required for stabilizing the association of Opi1p at the nuclear/ER membrane (66Loewen C.J.R. Gaspar M.L. Jesch S.A. Delon C. Ktistakis N.T. Henry S.A. Levine T.P. Science. 2004; 304: 1644-1647Crossref PubMed Scopus (369) Google Scholar). The establishment of this mechanism thus provided confirmation of the signaling role of PA predicted by the genetic experiments described above (31Henry S.A. Patton-Vogt J.L. Prog. Nucleic Acid Res. 1998; 61: 133-179Crossref PubMed Google Scholar). Changes in PA concentration can be brought about by the action and regulation of several enzymes (e.g. CDP-DAG pathway enzymes, Kennedy pathway enzymes, Mg2+-dependent PA phosphatase, and phospholipase D) and thus are predicted to affect the location and repressor activity of Opi1p. As discussed below, this also explains why the expression of UASINO-containing genes is regulated by growth phase and nutrient depletion (e.g. nitrogen and zinc), conditions that lower PA levels, independent of inositol availability. A model for the regulation of UASINO-containing genes by inositol and by nutrient depletion is presented in Fig. 2. According to this model, Opi1p is associated with the nuclear/ER membrane through interactions with PA and Scs2p when exponential phase cells are grown without inositol and in the presence of sufficient amounts of essential nutrients (e.g. zinc) (Fig. 2A). Upon inositol supplementation, exponential phase cells synthesize an elevated level of PI through increased substrate availability (71Kelley M.J. Bailis A.M. Henry S.A. Carman G.M. J. Biol. Chem. 1988; 263: 18078-18085Abstract Full Text PDF PubMed Google Scholar) and draw upon the pool of PA at the nuclear/ER membrane (Fig. 2B) (66Loewen C.J.R. Gaspar M.L. Jesch S.A. Delon C. Ktistakis N.T. Henry S.A. Levine T.P. Science. 2004; 304: 1644-1647Crossref PubMed Scopus (369) Google Scholar). At the same time, inositol supplementation results in an increase in Mg2+-dependent PA phosphatase activity (72Morlock K.R. Lin Y.-P. Carman G.M. J. Bacteriol. 1988; 170: 3561-3566Crossref PubMed Google Scholar), which contributes to the decrease in the PA pool. TAG is synthesized at the expense of glycerophospholipids in stationary phase cells (73Taylor F.R. Parks L.W. Biochim. Biophys. Acta. 1979; 575: 204-214Crossref PubMed Scopus (54) Google Scholar), and Mg2+-dependent PA phosphatase activity is elevated under this growth condition (74Hosaka K. Yamashita S. Biochim. Biophys. Acta. 1984; 796: 110-117Crossref PubMed Scopus (48) Google Scholar). The PAH1-encoded Mg2+-dependent PA phosphatase enzyme plays a major role in TAG synthesis, and its increased activity in stationary phase diminishes the PA pool (62Han G.-S. Wu W.-I. Carman G.M. J. Biol. Chem. 2006; 281: 9210-9218Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar). In zincdepleted cells, PI synthesis increases (75Iwanyshyn W.M. Han G.-S. Carman G.M. J. Biol. Chem. 2004; 279: 21976-21983Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar), and this condition should draw upon the PA pool. The increase in PI synthesis in response to zinc depletion is not the result of elevated levels of inositol; INO1 is actually repressed under this growth condition (75Iwanyshyn W.M. Han G.-S. Carman G.M. J. Biol. Chem. 2004; 279: 21976-21983Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar). Instead, the increase in PI synthesis is due to the Zap1pmediated induction of PIS1 gene expression (76Han S.-H. Han G.-S. Iwanyshyn W.M. Carman G.M. J. Biol. Chem. 2005; 280: 29017-29024Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Furthermore, zinc depletion induces Mg2+-dependent PA phosphatase activity (77Iwanyshyn, W. M. (2005) Regulation of Phospholipid Synthesis in Saccharomyces cerevisiae by Zinc. Ph.D. dissertation, Rutgers University, New Brunswick, NJGoogle Scholar), and this would further reduce the PA pool. Thus, regardless of whether cells are supplemented with inositol or are depleted of an essential nutrient, a decrease in the PA level results in loss of Opi1p association with the nuclear/ER membrane, followed by Opi1p translocation into the nucleus. In the nucleus, Opi1p mediates repression of the UASINO-containing glycerophospholipid synthesis genes that are co-regulated through its interaction with Ino2p. The control of enzymes (e.g. CDP-DAG synthase, Mg2+-dependent PA phosphatase, and phospholipase D) that directly contribute to the PA pool at the nuclear/ER membrane should have a major impact on glycerophospholipid synthesis regulation by Opi1p. As indicated above, the phosphorylation state of Mg2+-dependent PA phosphatase plays a role in the Opi1p-mediated regulation of INO1 and OPI3 (64O'Hara L. Han G.-S. Peak-Chew S. Grimsey N. Carman G.M. Siniossoglou S. J. Biol. Chem. 2006; 281: 34537-34548Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). However, it is unclear how various growth conditions (e.g. inositol supplementation and zinc depletion) affect the phosphorylation-dephosphorylation of the enzyme. Opi1p is phosphorylated by protein kinase A (78Sreenivas A. Carman G.M. J. Biol. Chem. 2003; 278: 20673-20680Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar), protein kinase C (79Sreenivas A. Villa-Garcia M.J. Henry S.A. Carman G.M. J. Biol. Chem. 2001; 276: 29915-29923Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar), and casein kinase II (80Chang Y.-F. Carman G.M. J. Biol. Chem. 2006; 281: 4754-4761Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Phosphorylation by protein kinase A and casein kinase II stimulates Opi1p repressor function (78Sreenivas A. Carman G.M. J. Biol. Chem. 2003; 278: 20673-20680Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 80Chang Y.-F. Carman G.M. J. Biol. Chem. 2006; 281: 4754-4761Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar), whereas phosphorylation by protein kinase C attenuates Opi1p repressor function (79Sreenivas A. Villa-Garcia M.J. Henry S.A. Carman G.M. J. Biol. Chem. 2001; 276: 29915-29923Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). Whether these phosphorylation events influence the interaction of Opi1p with PA, Scs2p, or Ino2p is unclear. Inositol auxotrophy has been described in conjunction with mutations in several major signaling pathways that include the unfolded protein response (81Nikawa J. Yamashita S. Mol. Microbiol. 1992; 6: 1441-1446Crossref PubMed Scopus (157) Google Scholar, 82Cox J.S. Shamu C.E. Walter P. Cell. 1993; 73: 1197-1206Abstract Full Text PDF PubMed Scopus (943) Google Scholar, 83Chang H.J. Jesch S.A. Gaspar M.L. Henry S.A. Genetics. 2004; 168: 1899-1913Crossref PubMed Scopus (56) Google Scholar), the protein kinase C/mitogen-activated protein kinase (MAPK) pathway (84Nunez, L. R. (2006) Phospholipid Synthesis in Yeast: The Role of the PKC1-MPK1 Signal Transduction Pathway. Ph.D. dissertation, Cornell University, Ithaca, NYGoogle Scholar), and the glucose response pathway (85Shirra M.K. Patton-Vogt J. Ulrich A. Liuta-Tehlivets O. Kohlwein S.D. Henry S.A. Arndt K.M. Mol. Cell. Biol. 2001; 21: 5710-5722Crossref PubMed Scopus (84) Google Scholar). These observations have led to the speculation that these signaling pathways might play a direct role in transmitting the signal controlling INO1 expression. The demonstration that Opi1p translocation into the nucleus following inositol supplementation in response to PA availability is the major signal for repression of UASINO-containing genes indicates that these signaling pathways must play a more peripheral role. Such roles could include modulation of Opi1p activity by phosphorylation, as suggested for protein kinase C (79Sreenivas A. Villa-Garcia M.J. Henry S.A. Carman G.M. J. Biol. Chem. 2001; 276: 29915-29923Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar), or by influencing histone phosphorylation and subsequent acetylation at the INO1 locus, as suggested for the glucose response pathway (86Lo W.S. Duggan L. Emre N.C. Belotserkovskya R. Lane W.S. Shiekhattar R. Berger S.L. Science. 2001; 293: 1142-1146Crossref PubMed Scopus (296) Google Scholar, 87Lo W.S. Gamache E.R. Henry K.W. Yang D. Pillus L. Berger S.L. EMBO J. 2005; 24: 997-1008Crossref PubMed Scopus (79) Google Scholar). However, effects on histone modification at INO1 cannot fully explain the inositol auxotrophy of snf1 and snf4 mutants defective in the glucose response pathway because these phenotypes can be suppressed by direct inhibition of the enzymatic activity of acetyl-CoA carboxylase (85Shirra M.K. Patton-Vogt J. Ulrich A. Liuta-Tehlivets O. Kohlwein S.D. Henry S.A. Arndt K.M. Mol. Cell. Biol. 2001; 21: 5710-5722Crossref PubMed Scopus (84) Google Scholar), the enzyme controlling the rate-limiting step in fatty acid synthesis. Acetyl-CoA carboxylase is a direct target of Snf1p (related to mammalian AMP-activated protein kinase) in both yeast and mammals (88Woods A. Munday M.R. Scott J. Yang X. Carlson M. Carling D. J. Biol. Chem. 1994; 269: 19509-19515Abstract Full Text PDF PubMed Google Scholar). Thus, additional signals coming from fatty acid synthesis may also influence INO1 expression. It is quite possible that these signals are also coordinated through the de novo synthesis of PA because acyl-CoAs serve as immediate precursors. Future work on the coordination of lipid metabolism with other cellular processes, such as membrane trafficking and responses to stress and nutrient availability, via the major signaling pathways should provide new insights into the myriad roles of PA in the cell. These insights should provide models of metabolic regulation and lipid signaling testable in both animals and plants. We thank Yu-Fang Chang, Lorena Egüez, M. Laura Gaspar, Gil-Soo Han, Stephen A. Jesch, and Manual J. Villa-Garcia for helpful comments on the manuscript.

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