Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase

Goldstein JL, Brown MS . Regulation of the mevalonate pathway. Nature 1990; 343:425–430.

Brown MS, Goldstein JL . Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res 1980; 21:505–517.

Endo A, Kuroda M, Tanzawa K . Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett 1976; 72:323–326.

Brown MS, Faust JR, Goldstein JL . 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 1978; 253:1121–1128.

Nakanishi M, Goldstein JL, Brown MS . 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 1988; 263:8929–8937.

Horton JD, Goldstein JL, Brown MS . SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109:1125–1131.

Roitelman J, Simoni RD . Distinct sterol and nonsterol signals for the regulated degradation of 3-hydroxy-3-methylglutaryl-CoA reductase. J Biol Chem 1992; 267:25264–25273.

McGee TP, Cheng HH, Kumagai H, Omura S, Simoni RD . Degradation of 3-hydroxy-3-methylglutaryl-CoA reductase in endoplasmic reticulum membranes is accelerated as a result of increased susceptibility to proteolysis. J Biol Chem 1996; 271:25630–25638.

Ravid T, Doolman R, Avner R, Harats D, Roitelman J . The ubiquitin-proteasome pathway mediates the regulated degradation of mammalian 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 2000; 275:35840–35847.

Ness GC, Spindler CD, Moffler MH . Purification of 3-hydroxy-3-methylglutaryl coenzyme A reductase from rat liver. Arch Biochem Biophys 1979; 197:493–499.

Edwards PA, Lemongello D, Fogelman AM . Purification and properties of rat liver 3-hydroxy-3-methylglutaryl coenzyme A reductase. Biochim Biophys Acta 1979; 574:123–135.

Brown MS, Dana SE, Dietschy JM, Siperstein MD . 3-Hydroxy-3-methylglutaryl coenzyme A reductase. Solubilization and purification of a cold-sensitive microsomal enzyme. J Biol Chem 1973; 248:4731–4738.

Liscum L, Finer-Moore J, Stroud RM, et al. Domain structure of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a glycoprotein of the endoplasmic reticulum. J Biol Chem 1985; 260:522–530.

Roitelman J, Olender EH, Bar-Nun S, Dunn Jr WA, Simoni RD . 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 1992; 117:959–973.

Luskey KL, Stevens B . Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains responsible for catalytic activity and sterol-regulated degradation. J Biol Chem 1985; 260:10271–10277.

Gertler FB, Chiu CY, Richter-Mann L, Chin DJ . Developmental and metabolic regulation of the Drosophila melanogaster 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mol Cell Biol 1988; 8:2713–2721.

Gil G, Faust JR, Chin DJ, Goldstein JL, Brown MS . Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzyme. Cell 1985; 41:249–258.

Skalnik DG, Narita H, Kent C, Simoni RD . 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 1988; 263:6836–6841.

Inoue S, Bar-Nun S, Roitelman J, Simoni RD . Inhibition of degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo by cysteine protease inhibitors. J Biol Chem 1991; 266:13311–13317.

Hampton RY . Genetic analysis of hydroxymethylglutaryl-coenzyme A reductase regulated degradation. Curr Opin Lipidol 1998; 9:93–97.

Hampton RY, Koning A, Wright R, Rine J . In vivo examination of membrane protein localization and degradation with green fluorescent protein. Proc Natl Acad Sci USA 1996; 93:828–833.

Hampton RY . Proteolysis and sterol regulation. Annu Rev Cell Dev Biol 2002; 18:345–378.

Hampton RY . ER-associated degradation in protein quality control and cellular regulation. Curr Opin Cell Biol 2002; 14:476–482.

Nohturfft A, Brown MS, Goldstein JL . Topology of SREBP cleavage-activating protein, a polytopic membrane protein with a sterol-sensing domain. J Biol Chem 1998; 273:17243–17250.

Hua X, Nohturfft A, Goldstein JL, Brown MS . Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell 1996; 87:415–426.

Rawson RB, DeBose-Boyd R, Goldstein JL, Brown MS . Failure to cleave sterol regulatory element-binding proteins (SREBPs) causes cholesterol auxotrophy in Chinese hamster ovary cells with genetic absence of SREBP cleavage-activating protein. J Biol Chem 1999; 274:28549–28556.

DeBose-Boyd RA, Brown MS, Li WP, et al. Transport-dependent proteolysis of SREBP: relocation of site-1 protease from Golgi to ER obviates the need for SREBP transport to Golgi. Cell 1999; 99:703–712.

Nohturfft A, Yabe D, Goldstein JL, Brown MS, Espenshade PJ . Regulated step in cholesterol feedback localized to budding of SCAP from ER membranes. Cell 2000; 102:315–323.

Goldstein JL, DeBose-Boyd RA, Brown MS . Protein sensors for membrane sterols. Cell 2006; 124:35–46.

Yang T, Espenshade PJ, Wright ME, et al. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 2002; 110:489–500.

Yabe D, Brown MS, Goldstein JL . Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proc Natl Acad Sci USA 2002; 99:12753–12758.

Sun LP, Seemann J, Goldstein JL, Brown MS . 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 2007; 104:6519–6526.

Kuwabara PE, Labouesse M . The sterol-sensing domain: multiple families, a unique role? Trends Genet 2002; 18:193–201.

Yabe D, Xia ZP, Adams CM, Rawson RB . Three mutations in sterol-sensing domain of SCAP block interaction with insig and render SREBP cleavage insensitive to sterols. Proc Natl Acad Sci USA 2002; 99:16672–16677.

Nohturfft A, Hua X, Brown MS, Goldstein JL . 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 1996; 93:13709–13714.

Nohturfft A, Brown MS, Goldstein JL . 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 1998; 95:12848–12853.

Sever N, Yang T, Brown MS, Goldstein JL, DeBose-Boyd RA . Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol Cell 2003; 11:25–33.

Sever N, Song BL, Yabe D, et al. Insig-dependent ubiquitination and degradation of mammalian 3-hydroxy-3-methylglutaryl-CoA reductase stimulated by sterols and geranylgeraniol. J Biol Chem 2003; 278:52479–52490.

Lee PC, Sever N, DeBose-Boyd RA . Isolation of sterol-resistant Chinese hamster ovary cells with genetic deficiencies in both Insig-1 and Insig-2. J Biol Chem 2005; 280:25242–25249.

Song BL, DeBose-Boyd RA . Ubiquitination of 3-hydroxy-3-methylglutaryl-CoA reductase in permeabilized cells mediated by cytosolic E1 and a putative membrane-bound ubiquitin ligase. J Biol Chem 2004; 279:28798–28806.

Pickart CM . Mechanisms underlying ubiquitination. Annu Rev Biochem 2001; 70:503–533.

Weissman AM . Themes and variations on ubiquitylation. Nat Rev Mol Cell Biol 2001; 2:169–178.

Hershko A, Heller H, Elias S, Ciechanover A . Components of ubiquitin-protein ligase system. Resolution, affinity purification, and role in protein breakdown. J Biol Chem 1983; 258:8206–8214.

Hershko A, Heller H, Eytan E, Reiss Y . The protein substrate binding site of the ubiquitin-protein ligase system. J Biol Chem 1986; 261:11992–11999.

Hershko A, Ciechanover A, Varshavsky A . Basic Medical Research Award. The ubiquitin system. Nat Med 2000; 6:1073–1081.

Song BL, Sever N, DeBose-Boyd RA . Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol Cell 2005; 19:829–840.

Lorick KL, Jensen JP, Fang S, et al. RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci USA 1999; 96:11364–11369.

Ponting CP . Proteins of the endoplasmic-reticulum-associated degradation pathway: domain detection and function prediction. Biochem J 2000; 351 Pt 2:527–535.

Cao J, Wang J, Qi W, et al. Ufd1 is a cofactor of gp78 and plays a key role in cholesterol metabolism by regulating the stability of HMG-CoA reductase. Cell Metab 2007; 6:115–128.

Ye Y, Meyer HH, Rapoport TA . The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 2001; 414:652–656.

Gong Y, Lee JN, Lee PC, et al. Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Cell Metab 2006; 3:15–24.

Lee JN, Song B, DeBose-Boyd RA, Ye J . Sterol-regulated degradation of Insig-1 mediated by the membrane-bound ubiquitin ligase gp78. J Biol Chem 2006; 281:39308–39315.

Schroepfer Jr GJ . Oxysterols: modulators of cholesterol metabolism and other processes. Physiol Rev 2000; 80:361–554.

Bjorkhem I . Do oxysterols control cholesterol homeostasis? J Clin Invest 2002; 110:725–730.

Russell DW . Oxysterol biosynthetic enzymes. Biochim Biophys Acta (BBA) Mol Cell Biol Lipids 2000; 1529:126–135.

Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL . Direct binding of cholesterol to the purified membrane region of SCAP; mechanism for a sterol-sensing domain. Mol Cell 2004; 15:259–268.

Adams CM, Goldstein JL, Brown MS . Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles. Proc Natl Acad Sci USA 2003; 100:10647–10652.

Brown AJ, Sun L, Feramisco JD, Brown MS, Goldstein JL . Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol Cell 2002; 10:237–245.

Radhakrishnan A, Ikeda Y, Kwon HJ, Brown MS, Goldstein JL . From the Cover: Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to Insig. PNAS 2007; 104:6511–6518.

Chen HW, Leonard DA, Fischer RT, Trzaskos JM . A mammalian mutant cell lacking detectable lanosterol 14 alpha-methyl demethylase activity. J Biol Chem 1988; 263:1248–1254.

Leonard DA, Kotarski MA, Tessiatore JE, Favata MF, Trzaskos JM . Post-transcriptional regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase by 3 beta-hydroxy-lanost-8-en-32-al, an intermediate in the conversion of lanosterol to cholesterol. Arch Biochem Biophys 1994; 310:152–157.

Song BL, Javitt NB, DeBose-Boyd RA . Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol. Cell Metabolism 2005; 1:179–189.

Gaylor JL . Membrane-bound enzymes of cholesterol synthesis from Lanosterol. Biochem Biophys Res Commun 2002; 292:1139–1146.

Williams MT, Gaylor JL, Morris HP . Investigation of the rate-determining microsomal reaction of cholesterol biosynthesis from lanosterol in Morris hepatomas and liver. Cancer Res 1977; 37:1377–1383.

Xu F, Rychnovsky SD, Belani JD, et al. Dual roles for cholesterol in mammalian cells. Proc Natl Acad Sci USA 2005; 102:14551–14556.

Nguyen AD, McDonald JG, Bruick RK, DeBose-Boyd RA . Hypoxia stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase through accumulation of lanosterol and hypoxia-inducible factor-mediated induction of insigs. J Biol Chem 2007; 282:27436–27446.

Maxwell PH, Wiesener MS, Chang GW, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399:271–275.

Epstein AC, Gleadle JM, McNeill LA, et al. C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001; 107:43–54.

Bruick RK, McKnight SL . A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001; 294:1337–1340.

Schofield CJ, Ratcliffe PJ . Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol 2004; 5:343–354.

Semenza GL . Hydroxylation of HIF-1: oxygen sensing at the molecular level. Physiology (Bethesda) 2004; 19:176–182.

Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292:468–472.

Kim H, Lee DK, Choi JW, et al. Analysis of the effect of aging on the response to hypoxia by cDNA microarray. Mech Ageing Dev 2003; 124:941–949.

Mense SM, Sengupta A, Zhou M, et al. Gene expression profiling reveals the profound upregulation of hypoxia-responsive genes in primary human astrocytes. Physiol Genom 2006; 25:435–449.

Sung FL, Hui EP, Tao Q, et al. Genome-wide expression analysis using microarray identified complex signaling pathways modulated by hypoxia in nasopharyngeal carcinoma. Cancer Lett 2007; 253:74–88.

Song BL, DeBose-Boyd RA . Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. J Biol Chem 2006; 281:25054–25061.

Sever N, Lee PCW, Song BL, Rawson RB, DeBose-Boyd RA . 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 2004; 279:43136–43147.

Seabra MC, Mules EH, Hume AN . Rab GTPases, intracellular traffic and disease. Trends Mol Med 2002; 8:23–30.

Engelking LJ, Liang G, Hammer RE, et al. Schoenheimer effect explained – feedback regulation of cholesterol synthesis in mice mediated by Insig proteins. J Clin Invest 2005; 115:2489–2498.

Illingworth DR, Tobert JA . HMG-CoA reductase inhibitors. Adv Protein Chem 2001; 56:77–114.

Kita T, Brown MS, Goldstein JL . 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 1980; 66:1094–1100.

Singer II, Kawka DW, Kazazis DM, et al. Hydroxymethylglutaryl-coenzyme A reductase-containing hepatocytes are distributed periportally in normal and mevinolin-treated rat livers. Proc Natl Acad Sci USA 1984; 81:5556–5560.

Reihner E, Rudling M, Stahlberg D, et al. Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol. N Engl J Med 1990; 323:224–228.