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• W2002192641 abstract "Intracellular cholesterol redistribution between membranes and its subsequent esterification are critical aspects of lipid homeostasis that prevent free sterol toxicity. To identify genes that mediate sterol trafficking, we screened for yeast mutants that were inviable in the absence of sterol esterification. Mutations in the novel gene, ARV1, render cells dependent on sterol esterification for growth, nystatin-sensitive, temperature-sensitive, and anaerobically inviable. Cells lacking Arv1p display altered intracellular sterol distribution and are defective in sterol uptake, consistent with a role for Arv1p in trafficking sterol into the plasma membrane. Human ARV1, a predicted sequence ortholog of yeast ARV1, complements the defects associated with deletion of the yeast gene. The genes are predicted to encode transmembrane proteins with potential zinc-binding motifs. We propose that ARV1 is a novel mediator of eukaryotic sterol homeostasis. Intracellular cholesterol redistribution between membranes and its subsequent esterification are critical aspects of lipid homeostasis that prevent free sterol toxicity. To identify genes that mediate sterol trafficking, we screened for yeast mutants that were inviable in the absence of sterol esterification. Mutations in the novel gene, ARV1, render cells dependent on sterol esterification for growth, nystatin-sensitive, temperature-sensitive, and anaerobically inviable. Cells lacking Arv1p display altered intracellular sterol distribution and are defective in sterol uptake, consistent with a role for Arv1p in trafficking sterol into the plasma membrane. Human ARV1, a predicted sequence ortholog of yeast ARV1, complements the defects associated with deletion of the yeast gene. The genes are predicted to encode transmembrane proteins with potential zinc-binding motifs. We propose that ARV1 is a novel mediator of eukaryotic sterol homeostasis. acyl-coenzyme A:cholesterol O-acyltransferase low density lipoprotein sterol regulatory element-binding protein(s) plasma membrane endoplasmic reticulum Yeast extract-peptone dextrose synthetic complete dextrose 5-fluoro orotic acid base pair polymerase chain reaction Arv1 homology domain Sterols are essential structural and regulatory components of eukaryotic cellular membranes (1Bloch K.E. CRC Crit. Rev. Biochem. 1983; 14: 47-92Crossref PubMed Scopus (514) Google Scholar, 2Parks L.W. Smith S.J. Crowley J.H. Lipids. 1995; 30: 227-230Crossref PubMed Scopus (104) Google Scholar). However, cholesterol over-accumulation is cytotoxic (3Jackson R.L. Gotto A.M.J. Atherosclerosis. 1976; 1: 1-21Google Scholar), necessitating mechanisms to maintain this metabolite at appropriate levels. A pivotal component of this homeostasis is the esterification of free sterol by acyl-coenzyme A:cholesterol O-acyltransferase (ACAT)1 (4Chang T.-Y. Doolittle G.M. Boyer P. The Enzymes. Academic Press, New York1983: 523-539Google Scholar, 5Xu X.X. Tabas I. J. Biol. Chem. 1991; 266: 17040-17048Abstract Full Text PDF PubMed Google Scholar). Indeed, the inhibition of ACAT in sterol-loaded cells induces cell death when extracellular sterol acceptors such as high density lipoproteins are absent (6Warner G.J. Stoudt G. Bamberger M. Johnson W.J. Rothblat G.H. J. Biol. Chem. 1995; 270: 5772-5778Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 7Kellner-Weibel G. Geng Y.J. Rothblat G.H. Atherosclerosis. 1999; 146: 309-319Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar).Intracellular cholesterol redistribution mediates a number of responses to elevated free sterol levels. These include elevated ACAT activity, down-regulated sterol and fatty acid biosynthesis, and reduced lipoprotein uptake via LDL receptors (8Tabas I. Weiland D.A. Tall A.R. J. Biol. Chem. 1986; 261: 3147-3155Abstract Full Text PDF PubMed Google Scholar, 9Brown M.S. Goldstein J.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11041-11048Crossref PubMed Scopus (1093) Google Scholar). The latter two events reflect changes in transcriptional activation by sterol regulatory element-binding proteins (SREBPs) in response to sterol accumulation in regulatory pools (9Brown M.S. Goldstein J.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11041-11048Crossref PubMed Scopus (1093) Google Scholar), whereas ACAT activity is allosterically regulated by substrate supply (10Cheng D. Chang C.C. Qu X. Chang T.Y. J. Biol. Chem. 1995; 270: 685-695Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). Sterols are maintained at a high concentration in the plasma membrane (PM) relative to the endoplasmic reticulum (ER) (1Bloch K.E. CRC Crit. Rev. Biochem. 1983; 14: 47-92Crossref PubMed Scopus (514) Google Scholar, 2Parks L.W. Smith S.J. Crowley J.H. Lipids. 1995; 30: 227-230Crossref PubMed Scopus (104) Google Scholar), where SREBP and ACAT reside. Thus trafficking of sterol to and from the ER is a critical component of sterol homeostasis.The process of sterol trafficking is poorly understood at the molecular level. In certain cell types, caveolin influences what has been termed “fast” movement of cholesterol to plasma membrane cholesterol-rich microdomains (caveolae) (11Smart E.J. Ying Y. Donzell W.C. Anderson R.G. J. Biol. Chem. 1996; 271: 29427-29435Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar, 12Uittenbogaard A. Ying Y. Smart E.J. J. Biol. Chem. 1998; 273: 6525-6532Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). Mutations in the NiemannPick type C (NPC1) gene result in accumulation of LDL-derived cholesterol in the lysosome (13Carstea E.D. et al.Science. 1997; 277: 228-231Crossref PubMed Scopus (1199) Google Scholar, 14Loftus S.K. Morris J.A. Carstea E.D. Gu J.Z. Cummings C. Brown A. Ellison J. Ohno K. Rosenfeld M.A. Tagle D.A. Pentchev P.G. Pavan W.J. Science. 1997; 277: 232-235Crossref PubMed Scopus (692) Google Scholar). However, not all cells express caveolin, and the movement of endogenously synthesized cholesterol to the plasma membrane in NPC1-deficient cells is normal (15Cruz J.C. Chang T.Y. J. Biol. Chem. 2001; 276: 41309-41316Abstract Full Text Full Text PDF Scopus (43) Google Scholar).To identify novel genes that mediate sterol trafficking in all higher cells, we utilized the genetically tractable model eukaryote,Saccharomyces cerevisiae (budding yeast). We reasoned that dependence on sterol esterification for viability would be one criterion for identifying novel sterol-trafficking genes. Yeast strains lacking the ACAT-related enzymes (encoded by the ARE1 and ARE2 genes) contain no steryl ester (16Yang H. Bard M. Bruner D.A. Gleeson A. Deckelbaum R.J. Aljinovic G. Pohl T. Rothstein R. Sturley S.L. Science. 1996; 272: 1353-1356Crossref PubMed Scopus (223) Google Scholar, 17Yu C. Kennedy N.J. Chang C.C.Y. Rothblatt J.A. J. Biol. Chem. 1996; 271: 24157-24163Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar), down-regulate sterol biosynthesis (16Yang H. Bard M. Bruner D.A. Gleeson A. Deckelbaum R.J. Aljinovic G. Pohl T. Rothstein R. Sturley S.L. Science. 1996; 272: 1353-1356Crossref PubMed Scopus (223) Google Scholar, 18Arthington-Skaggs B.A. Crowell D.N. Yang H. Sturley S.L. Bard M. FEBS Lett. 1996; 392: 161-165Crossref PubMed Scopus (59) Google Scholar), and grow normally. In a screen for genes required for viability in the absence of the ARE genes, we isolated yeast and humanARV1 (ARE2 required forviability). We demonstrate that ARV1 is required for sterol uptake and distribution in yeast. Sterols are essential structural and regulatory components of eukaryotic cellular membranes (1Bloch K.E. CRC Crit. Rev. Biochem. 1983; 14: 47-92Crossref PubMed Scopus (514) Google Scholar, 2Parks L.W. Smith S.J. Crowley J.H. Lipids. 1995; 30: 227-230Crossref PubMed Scopus (104) Google Scholar). However, cholesterol over-accumulation is cytotoxic (3Jackson R.L. Gotto A.M.J. Atherosclerosis. 1976; 1: 1-21Google Scholar), necessitating mechanisms to maintain this metabolite at appropriate levels. A pivotal component of this homeostasis is the esterification of free sterol by acyl-coenzyme A:cholesterol O-acyltransferase (ACAT)1 (4Chang T.-Y. Doolittle G.M. Boyer P. The Enzymes. Academic Press, New York1983: 523-539Google Scholar, 5Xu X.X. Tabas I. J. Biol. Chem. 1991; 266: 17040-17048Abstract Full Text PDF PubMed Google Scholar). Indeed, the inhibition of ACAT in sterol-loaded cells induces cell death when extracellular sterol acceptors such as high density lipoproteins are absent (6Warner G.J. Stoudt G. Bamberger M. Johnson W.J. Rothblat G.H. J. Biol. Chem. 1995; 270: 5772-5778Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 7Kellner-Weibel G. Geng Y.J. Rothblat G.H. Atherosclerosis. 1999; 146: 309-319Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Intracellular cholesterol redistribution mediates a number of responses to elevated free sterol levels. These include elevated ACAT activity, down-regulated sterol and fatty acid biosynthesis, and reduced lipoprotein uptake via LDL receptors (8Tabas I. Weiland D.A. Tall A.R. J. Biol. Chem. 1986; 261: 3147-3155Abstract Full Text PDF PubMed Google Scholar, 9Brown M.S. Goldstein J.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11041-11048Crossref PubMed Scopus (1093) Google Scholar). The latter two events reflect changes in transcriptional activation by sterol regulatory element-binding proteins (SREBPs) in response to sterol accumulation in regulatory pools (9Brown M.S. Goldstein J.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 11041-11048Crossref PubMed Scopus (1093) Google Scholar), whereas ACAT activity is allosterically regulated by substrate supply (10Cheng D. Chang C.C. Qu X. Chang T.Y. J. Biol. Chem. 1995; 270: 685-695Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). Sterols are maintained at a high concentration in the plasma membrane (PM) relative to the endoplasmic reticulum (ER) (1Bloch K.E. CRC Crit. Rev. Biochem. 1983; 14: 47-92Crossref PubMed Scopus (514) Google Scholar, 2Parks L.W. Smith S.J. Crowley J.H. Lipids. 1995; 30: 227-230Crossref PubMed Scopus (104) Google Scholar), where SREBP and ACAT reside. Thus trafficking of sterol to and from the ER is a critical component of sterol homeostasis. The process of sterol trafficking is poorly understood at the molecular level. In certain cell types, caveolin influences what has been termed “fast” movement of cholesterol to plasma membrane cholesterol-rich microdomains (caveolae) (11Smart E.J. Ying Y. Donzell W.C. Anderson R.G. J. Biol. Chem. 1996; 271: 29427-29435Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar, 12Uittenbogaard A. Ying Y. Smart E.J. J. Biol. Chem. 1998; 273: 6525-6532Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). Mutations in the NiemannPick type C (NPC1) gene result in accumulation of LDL-derived cholesterol in the lysosome (13Carstea E.D. et al.Science. 1997; 277: 228-231Crossref PubMed Scopus (1199) Google Scholar, 14Loftus S.K. Morris J.A. Carstea E.D. Gu J.Z. Cummings C. Brown A. Ellison J. Ohno K. Rosenfeld M.A. Tagle D.A. Pentchev P.G. Pavan W.J. Science. 1997; 277: 232-235Crossref PubMed Scopus (692) Google Scholar). However, not all cells express caveolin, and the movement of endogenously synthesized cholesterol to the plasma membrane in NPC1-deficient cells is normal (15Cruz J.C. Chang T.Y. J. Biol. Chem. 2001; 276: 41309-41316Abstract Full Text Full Text PDF Scopus (43) Google Scholar). To identify novel genes that mediate sterol trafficking in all higher cells, we utilized the genetically tractable model eukaryote,Saccharomyces cerevisiae (budding yeast). We reasoned that dependence on sterol esterification for viability would be one criterion for identifying novel sterol-trafficking genes. Yeast strains lacking the ACAT-related enzymes (encoded by the ARE1 and ARE2 genes) contain no steryl ester (16Yang H. Bard M. Bruner D.A. Gleeson A. Deckelbaum R.J. Aljinovic G. Pohl T. Rothstein R. Sturley S.L. Science. 1996; 272: 1353-1356Crossref PubMed Scopus (223) Google Scholar, 17Yu C. Kennedy N.J. Chang C.C.Y. Rothblatt J.A. J. Biol. Chem. 1996; 271: 24157-24163Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar), down-regulate sterol biosynthesis (16Yang H. Bard M. Bruner D.A. Gleeson A. Deckelbaum R.J. Aljinovic G. Pohl T. Rothstein R. Sturley S.L. Science. 1996; 272: 1353-1356Crossref PubMed Scopus (223) Google Scholar, 18Arthington-Skaggs B.A. Crowell D.N. Yang H. Sturley S.L. Bard M. FEBS Lett. 1996; 392: 161-165Crossref PubMed Scopus (59) Google Scholar), and grow normally. In a screen for genes required for viability in the absence of the ARE genes, we isolated yeast and humanARV1 (ARE2 required forviability). We demonstrate that ARV1 is required for sterol uptake and distribution in yeast. We thank Richard Deckelbaum, Michael Hampsey, Jessica Rich, Rodney Rothstein, Ira Tabas, Alan Tall, and members of the Sturley laboratory for helpful discussions." @default.
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• W2002192641 title "Mutations in Yeast ARV1 Alter Intracellular Sterol Distribution and Are Complemented by Human ARV1" @default.
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