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Review Article

Control of cholesterol synthesis through regulated ER-associated degradation of HMG CoA reductase

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Pages 185-198 | Received 27 Jan 2010, Accepted 12 Apr 2010, Published online: 20 May 2010

References

  • Ahner A and Brodsky JL. 2004. Checkpoints in ER-associated degradation: excuse me, which way to the proteasome? Trends Cell Biol 14:474–478.
  • Altmann SW, Davis HR Jr Zhu, LJ, Yao X, Hoos LM, Tetzloff G., lyer S.P.N., Maguire M., Golovko A., Zeng M., et al. 2004. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 303:1201–1204.
  • Aridor M, 2007. Visiting the ER: The endoplasmic reticulum as a target for therapeutics in traffic related diseases. Adv Drug Deliver Rev 59:759–781.
  • Bartz R, Zehmer JK, Zhu M, Chen Y, Serrero G, Zhao Y and Liu P. 2007. Dynamic activity of lipid droplets: protein phosphorylation and GTP-mediated protein translocation 2. J Proteome Res 6:3256–3265.
  • Brodsky JL and Wojcikiewicz RJH. 2009. Substrate-specific mediators of ER associated degradation (ERAD). Current Opinion in Cell Biology 21:516–521.
  • Brown K, Havel CM and Watson JA. 1983. Isoprene synthesis in isolated embryonic Drosophila cells. II. Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity 47. J Biol Chem 258:8512–8518.
  • Brown MS and Goldstein JL. 1980. Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res 21:505–517.
  • Brown MS and Goldstein JL. 1986. A receptor-mediated pathway for cholesterol homeostasis. Science 232:34–47.
  • Brown MS, Faust JR and Goldstein JL. 1978. Induction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in human fibroblasts incubated with compactin (ML-236B), a competitive inhibitor of the reductase. J Biol Chem 253:1121–1128.
  • Buck TM, Wright CM and Brodsky JL. 2007. The activities and function of molecular chaperones in the endoplasmic reticulum. Semin Cell Dev Biol 18:751–761.
  • Burke R, Nellen D, Bellotto M, Hafen E, Senti KA, Dickson BJ and Basler K. 1999. Dispatched, a novel sterol-sensing domain protein dedicated to the release of cholesterol-modified Hedgehog from signaling cells. Cell 99:803–815.
  • Caramelo JJ and Parodi AJ. 2008. Getting in and out from calnexin/calreticulin cycles. J Biol Chem 283:10221–10225.
  • Carvalho P, Goder V and Rapoport TA. 2006. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126:361–373.
  • Christianson JC, Shaler TA, Tyler RE and Kopito RR. 2008. OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD 3. Nat Cell Biol 10:272–282.
  • Clark AJ and Bloch K. 1959. The absence of sterol synthesis in insects. J Biol Chem 234:2578–2582.
  • Clayton RB. 1964. The utilization of sterols by insects 1. J Lipid Res 15:3–19.
  • DeBose-Boyd RA, Brown MS, Li WP, Nohturfft A, Goldstein JL and Espenshade PJ. 1999. Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell 99:703–712.
  • Denic V, Quan EM and Weissman JS. 2006. A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell 126:349–359.
  • Deshaies RJ and Joazeiro CAP. 2009 RING domain E3 ubiquitin ligases. Ann Rev Biochem 78:399–434.
  • Eaton S. 2008. Multiple roles for lipids in the Hedgehog signalling pathway. Nat Rev Mol Cell Biol 9:437–445.
  • Endo A, Kuroda M and Tanzawa K. 1976a. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity 9. FEBS Lett 72:323–326.
  • Endo A, Kuroda M and Tsujita Y. 1976b. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium. J Antibiot (Tokyo) 29:1346–1348.
  • Endo A, Tsujita Y, Kuroda M and Tanzawa K. 1979. Effects of ML-236B on cholesterol metabolism in mice and rats: lack of hypocholesterolemic activity in normal animals. Biochim Biophys Acta 575:266–276.
  • Engelking LJ, Liang G, Hammer RE, Takaishi K, Kuriyama H, Evers BM, Li WP, Horton JD, Goldstein JL and Brown MS. 2005. Schoenheimer effect explained – feedback regulation of cholesterol synthesis in mice mediated by Insig proteins 1. J Clin Invest 115:2489–2498.
  • Flury I, Garza R, Shearer A, Rosen J, Cronin S et al. 2005. INSIG: a broadly conserved transmembrane chaperone for sterol-sensing domain proteins. EMBO J 24:3917–3926.
  • Gardner RG and Hampton RY. 1999. A ‘distributed degron’ allows regulated entry into the ER degradation pathway. EMBO J 18:5994–6004.
  • Gardner RG, Swarbrick GM, Bays NW, Cronin SR, Wilhovsky S, Seelig L, Kim C and Hampton RY. 2000. Endoplasmic reticulum degradation requires lumen to cytosol signaling. Transmembrane control of Hrd1p by Hrd3p. J Cell Biol 151:69–82.
  • Gardner RG, Shearer AG and Hampton RY. 2001. In vivo action of the HRD ubiquitin ligase complex: mechanisms of endoplasmic reticulum quality control and sterol regulation. Mol Cell Biol 21:4276–4291.
  • Garza RM, Sato BK and Hampton RY. 2009a. In vitro analysis of Hrd1p-mediated retrotranslocation of its multispanning membrane substrate 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase. J Biol Chem 284:14710–14722.
  • Garza RM, Tran PN and Hampton RY. 2009b. Geranylgeranyl pyrophosphate (GGPP) is a potent regulator of HRD-dependent HMG-CoA reductase degradation in yeast. J Biol Chem. 284: 35368-35380.
  • Gaylor JL. 2002. Membrane-bound enzymes of cholesterol synthesis from lanosterol. Biochem Bioph Res Co 292:1139–1146.
  • Gertler FB, Chiu CY, Richter-Mann L and Chin DJ. 1988. Developmental and metabolic regulation of the Drosophila melanogaster 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mol Cell Biol 8:2713–2721.
  • Gil G, Faust JR, Chin DJ, Goldstein JL and Brown MS. 1985. Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzyme. Cell 41:249–258.
  • Goldstein JL and Brown MS. 1990. Regulation of the mevalonate pathway. Nature 343:425–430.
  • Goldstein JL, DeBose-Boyd RA and Brown MS. 2006. Protein sensors for membrane sterols 1. Cell 124:35–46.
  • Hampton RY. 1998 Genetic analysis of hydroxymethylglutaryl-coenzyme A reductase regulated degradation. Curr Opin Lipidol 9:93–97.
  • Hampton RY and Bhakta H. 1997. Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase. Proc Natl Acad Sci USA 94:12944–12948.
  • Hampton RY and Garza RM. 2009. Protein quality control as a strategy for cellular regulation: lessons from ubiquitin-mediated regulation of the sterol pathway. Chem Rev 109:1561–1574.
  • Hampton RY, Koning A, Wright R and Rine J. 1996. In vivo examination of membrane protein localization and degradation with green fluorescent protein. Proc Natl Acad Sci USA 93:828–833.
  • Heart Protection Study Collaborative 2002 MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360:7–22.
  • Helenius A and Aebi M. 2004. Roles of N-linked glycans in the endoplasmic reticulum. Ann Rev Biochem 73:1019–1049.
  • Horton JD, Goldstein JL and Brown MS. 2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109:1125–1131.
  • Hua X, Nohturfft A, Goldstein JL and Brown MS. 1996. Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell 87:415–426.
  • Huh WK, Falvo JV, Gerke LC, Carroll AS, Howson RW, Weissman JS and O’Shea EK. 2003. Global analysis of protein localization in budding yeast. Nature 425:686–691.
  • Huppa JB and Ploegh HL. 1997. In vitro translation and assembly of a complete T cell receptor-CD3 complex. J Exp Med 186:393–403.
  • Ikeda Y, Demartino GN, Brown MS, Lee JN, Goldstein JL, and Ye J. 2009. Regulated endoplasmic reticulum-associated degradation of a polytopic protein: p97 recruits proteasomes to Insig-1 before extraction from membranes. J Biol Chem 284:34889–34900.
  • Inoue S, Bar-Nun S, Roitelman J and Simoni RD. 1991. Inhibition of degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo by cysteine protease inhibitors. J Biol Chem 266:13311–13317.
  • Jarosch E, Lenk U and Sommer T. 2003. Endoplasmic reticulum-associated protein degradation 15. Int Rev Cytol 223:39–81.
  • Kim TY, Kim E, Yoon SK and Yoon JB. 2008. Herp enhances ER-associated protein degradation by recruiting ubiquilins 1. Biochem Biophys Res Commun 369:741–746.
  • Kita T, Brown MS and Goldstein JL. 1980. Feedback regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in livers of mice treated with mevinolin, a competitive inhibitor of the reductase. J Clin Invest 66:1094–1100.
  • Ko HS, Uehara T, Tsuruma K and Nomura Y. 2004. Ubiquilin interacts with ubiquitylated proteins and proteasome through its ubiquitin-associated and ubiquitin-like domains 1. FEBS Lett 566:110–114.
  • Koegl M, Hoppe T, Schlenker S, Ulrich HD, Mayer TU and Jentsch S. 1999. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96:635–644.
  • Kostova Z, Tsai YC and Weissman AM. 2007. Ubiquitin ligases, critical mediators of endoplasmic reticulum-associated degradation. Semin Cell Dev Biol 18:770–779.
  • Kuwabara PE and Labouesse M. 2002. The sterol-sensing domain: multiple families, a unique role? Trends Genet 18:193–201.
  • Lange Y, Ory DS, Ye J, Lanier MH, Hsu FF and Steck TL. 2008. Effectors of rapid homeostatic responses of endoplasmic reticulum cholesterol and 3-hydroxy-3-methylglutaryl-CoA reductase 2. J Biol Chem 283:1445–1455.
  • Lee PC, Sever N and DeBose-Boyd RA. 2005. Isolation of sterol-resistant Chinese hamster ovary cells with genetic deficiencies in both Insig-1 and Insig-2 2. J Biol Chem 280:25242–25249.
  • Lee PC, Nguyen AD and DeBose-Boyd RA. 2007. Mutations within the membrane domain of HMG-CoA reductase confer resistance to sterol-accelerated degradation 1. J Lipid Res 48:318–327.
  • Leichner GS, Avner R, Harats D and Roitelman J. 2009. Dislocation of HMG-CoA reductase and Insig-1, two polytopic endoplasmic reticulum proteins, en route to proteasomal degradation. Mol Biol Cell 20:3330–3341.
  • Liang G, Li Q, Tang Y, Kokame K, Kikuchi T, Wu G and Chen XZ. 2008. Polycystin-2 is regulated by endoplasmic reticulum-associated degradation. Hum Mol Genet 17:1109–1119.
  • Lilley BN and Ploegh HL. 2004. A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429:834–840.
  • Liscum L, Finer-Moore J, Stroud RM, Luskey KL, Brown MS, and Goldstein JL. 1985. Domain structure of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a glycoprotein of the endoplasmic reticulum. J Biol Chem 260:522–530.
  • Liu P, Ying Y, Zhao Y, Mundy DI, Zhu M and Anderson RG. 2004. Chinese hamster ovary K2 cell lipid droplets appear to be metabolic organelles involved in membrane traffic 1. J Biol Chem 279:3787–3792.
  • Loftus SK, Morris JA, Carstea ED, Gu JZ, Cummings C, Brown A, Ellison J, Ohno K, Rosenfeld MA, Tagle DA, et al. 1997. Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277:232–235.
  • Luskey KL and Stevens B. 1985. Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains responsible for catalytic activity and sterol-regulated degradation. J Biol Chem 260:10271–10277.
  • Meusser B, Hirsch C, Jarosch E and Sommer T. 2005. ERAD: the long road to destruction. Nat Cell Biol 7:766–772.
  • Nakanishi M, Goldstein JL and Brown MS. 1988. Multivalent control of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mevalonate-derived product inhibits translation of mRNA and accelerates degradation of enzyme. J Biol Chem 263:8929–8937.
  • Nakatsukasa K and Brodsky JL. 2008. The recognition and retrotranslocation of misfolded proteins from the endoplasmic reticulum. Traffic 9:861–870.
  • Nakatsukasa K, Huyer G, Michaelis S and Brodsky JL. 2008. Dissecting the ER-associated degradation of a misfolded polytopic membrane protein. Cell 132:101–112.
  • Nguyen AD, McDonald JG, Bruick RK and DeBose-Boyd RA. 2007. Hypoxia stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase through accumulation of lanosterol and hypoxia-inducible factor-mediated induction of insigs 1. J Biol Chem 282:27436–27446.
  • Nguyen AD, Lee SH and DeBose-Boyd RA. 2009. Insig-mediated, sterol-accelerated degradation of the membrane domain of hamster 3-hydroxy-3-methylglutaryl-coenzyme A reductase in insect cells. J Biol Chem 284:26778–26788.
  • Nohturfft A, Hua X, Brown MS and Goldstein JL. 1996. Recurrent G-to-A substitution in a single codon of SREBP cleavage-activating protein causes sterol resistance in three mutant Chinese hamster ovary cell lines. Proc Natl Acad Sci USA 93:13709–13714.
  • Nohturfft A, Brown MS and Goldstein JL. 1998a. Sterols regulate processing of carbohydrate chains of wild-type SREBP cleavage-activating protein (SCAP), but not sterol-resistant mutants Y298C or D443N. Proc Natl Acad Sci USA 95:12848–12853.
  • Nohturfft A, Brown MS and Goldstein JL. 1998b. Topology of SREBP cleavage-activating protein, a polytopic membrane protein with a sterol-sensing domain. J Biol Chem 273:17243–17250.
  • Nohturfft A, Yabe D, Goldstein JL, Brown MS and Espenshade PJ. 2000. Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell 102:315–323.
  • Ohsaki Y, Cheng J, Fujita A, Tokumoto T and Fujimoto T. 2006. Cytoplasmic lipid droplets are sites of convergence of proteasomal and autophagic degradation of apolipoprotein B 1. Mol Biol Cell 17:2674–2683.
  • Pickart CM. 1997. Targeting of substrates to the 26S proteasome. FASEB J 11:1055–1066.
  • Raasi S and Wolf DH. 2007. Ubiquitin receptors and ERAD: A network of pathways to the proteasome. Semin Cell Dev Biol 18:780–791.
  • Radhakrishnan A, Sun LP, Kwon HJ, Brown MS and Goldstein JL. 2004. Direct binding of cholesterol to the purified membrane region of SCAP; mechanism for a sterol-sensing domain 1. Mol Cell 15:259–268.
  • Ravid T, Doolman R, Avner R, Harats D and Roitelman J. 2000. The ubiquitin-proteasome pathway mediates the regulated degradation of mammalian 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 275:35840–35847.
  • Reihner E, Rudling M, Stahlberg D, Berglund L, Ewerth S, Bjorkhem I, Einarsson K and Angelin B. 1990. Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol. N Engl J Med 323:224–228.
  • Reynolds GA, Goldstein JL and Brown MS. 1985. Multiple mRNAs for 3-hydroxy-3-methylglutaryl coenzyme A reductase determined by multiple transcription initiation sites and intron splicing sites in the 5'-untranslated region. J Biol Chem 260:10369–10377.
  • Roitelman J, Olender EH, Bar-Nun S, Dunn Jr WA and Simoni RD. 1992. Immunological evidence for eight spans in the membrane domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for enzyme degradation in the endoplasmic reticulum. J Cell Biol 117:959–973.
  • Sakai J, Nohturfft A, Cheng D, Ho YK, Brown MS and Goldstein JL. 1997, Identification of complexes between the COOH-terminal domains of sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein. J Biol Chem 272:20213–20221.
  • Sato BK, Schulz D, Do PH and Hampton RY. 2009. Misfolded membrane proteins are specifically recognized by the transmembrane domain of the Hrd1p ubiquitin ligase. Mol.Cell 34:212–222.
  • Scandinavian Simvastatin Study 1994. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344:1383–1389.
  • Schuberth C and Buchberger A. 2008. UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97. Cell Mol Life Sci 65:2360–2371.
  • Schulze A, Standera S, Buerger E, Kikkert M, Van Voorden S, Wiertz E, Koning F, Kloetzel PM and Seeger M. 2005. The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway 9. J Mol Biol 354:1021–1027.
  • Seabra MC, Mules EH and Hume AN. 2002. Rab GTPases, intracellular traffic and disease. Trends Mol Med 8:23–30.
  • Sever N, Song BL, Yabe D, Goldstein JL, Brown MS, et al. 2003a. Insig-dependent ubiquitination and degradation of mammalian 3-hydroxy-3-methylglutaryl-CoA reductase stimulated by sterols and geranylgeraniol. J Biol Chem 278:52479–52490.
  • Sever N, Yang T, Brown MS, Goldstein JL and DeBose-Boyd RA. 2003b. Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol Cell 11:25–33.
  • Sever N, Lee PCW, Song BL, Rawson RB and DeBose-Boyd RA. 2004. Isolation of mutant cells lacking Insig-1 through selection with SR-12813, an agent that stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 279:43136–43147.
  • Shearer AG and Hampton RY. 2005. Lipid-mediated, reversible misfolding of a sterol-sensing domain protein 12. EMBO J 24:149–159.
  • Shmueli A, Tsai YC, Yang M, Braun MA and Weissman AM. 2009. Targeting of gp78 for ubiquitin-mediated proteasomal degradation by Hrd1: cross-talk between E3s in the endoplasmic reticulum. Biochem Bioph Res Co 390:758–762.
  • Singer II, Kawka DW, Kazazis DM, Alberts AW, Chen JS, Huff JW and Ness GC. 1984. Hydroxymethylglutaryl-coenzyme A reductase-containing hepatocytes are distributed periportally in normal and mevinolin-treated rat livers. Proc Natl Acad Sci USA 81:5556–5560.
  • Skalnik DG, Narita H, Kent C and Simoni RD. 1988. The membrane domain of 3-hydroxy-3-methylglutaryl-coenzyme A reductase confers endoplasmic reticulum localization and sterol-regulated degradation onto beta-galactosidase. J Biol Chem 263:6836–6841.
  • Song BL and DeBose-Boyd RA. 2004. Ubiquitination of 3-hydroxy-3-methylglutaryl-CoA reductase in permeabilized cells mediated by cytosolic E1 and a putative membrane-bound ubiquitin ligase 1. J Biol Chem 279:28798–28806.
  • Song BL, Javitt NB and DeBose-Boyd RA. 2005a. Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol. Cell Metabolism 1:179–189.
  • Song BL, Sever N and DeBose-Boyd RA. 2005b. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase 1. Mol Cell 19:829–840.
  • Sun LP, Seemann J, Goldstein JL and Brown MS. 2007. From the cover: sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins. Proc Natl Acad Sci USA 104:6519–6526.
  • VanSlyke JK and Musil LS. 2002. Dislocation and degradation from the ER are regulated by cytosolic stress. J Cell Biol 157:381–394.
  • VanSlyke JK, Deschenes SM and Musil LS. 2000. Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins. Mol Biol Cell 11:1933–1946.
  • Vembar SS and Brodsky JL. 2008. One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 9:944–957.
  • Vij N. 2008. AAA ATPase p97/VCP: cellular functions, disease and therapeutic potential. J Cell Mol Med 12:2511–2518.
  • Wahlman J, DeMartino GN, Skach WR, Bulleid NJ, Brodsky JL and Johnson Arthur E. 2007. Real-time fluorescence detection of ERAD substrate retrotranslocation in a mammalian in vitro system. Cell 129:943–955.
  • Walters KJ, Goh AM, Wang Q, Wagner G and Howley PM. 2004. Ubiquitin family proteins and their relationship to the proteasome: a structural perspective 1. Biochim Biophys Acta 1695:73–87.
  • Ward CL, Omura S and Kopito RR. 1995. Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 83:121–127.
  • Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ and Ploegh HL. 1996a. The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84:769–779.
  • Wiertz EJ, Tortorella D, Bogyo M, Yu J, Mothes W, Jones TR, Rapoport TA and Ploegh HL. 1996b. Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384:432–438.
  • Williams MT, Gaylor JL and Morris HP. 1977. Investigation of the rate-determining microsomal reaction of cholesterol biosynthesis from lanosterol in Morris hepatomas and liver 1. Cancer Res 37:1377–1383.
  • Yabe D, Brown MS and Goldstein JL. 2002a. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc Natl Acad Sci USA 99:12753–12758.
  • Yabe D, Xia ZP, Adams CM and Rawson RB. 2002b. Three mutations in sterol-sensing domain of SCAP block interaction with insig and render SREBP cleavage insensitive to sterols. Proc Natl Acad Sci USA 99:16672–16677.
  • Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL and Brown MS. 2002. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110:489–500.
  • Ye Y, Meyer HH and Rapoport TA. 2001. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol 25. Nature 414:652–656.
  • Ye Y, Shibata Y, Yun C, Ron D and Rapoport TA. 2004. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol 6. Nature 429:841–847.
  • Ye Y, Shibata Y, Kikkert M, Van Voorden S, Wiertz E and Rapoport TA. 2005. Inaugural article: recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane 1. Proc Natl Acad Sci USA 102:14132–14138.

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