Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

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

Cell Research volume 18, pages 609–621 (2008) Cite this article

Abstract

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase produces mevalonate, an important intermediate in the synthesis of cholesterol and essential nonsterol isoprenoids. The reductase is subject to an exorbitant amount of feedback control through multiple mechanisms that are mediated by sterol and nonsterol end-products of mevalonate metabolism. Here, I will discuss recent advances that shed light on one mechanism for control of reductase, which involves rapid degradation of the enzyme. Accumulation of certain sterols triggers binding of reductase to endoplasmic reticulum (ER) membrane proteins called Insig-1 and Insig-2. Reductase-Insig binding results in recruitment of a membrane-associated ubiquitin ligase called gp78, which initiates ubiquitination of reductase. This ubiquitination is an obligatory reaction for recognition and degradation of reductase from ER membranes by cytosolic 26S proteasomes. Thus, sterol-accelerated degradation of reductase represents an example of how a general cellular process (ER-associated degradation) is used to control an important metabolic pathway (cholesterol synthesis).

Log in or create a free account to read this content

Gain free access to this article, as well as selected content from this journal and more on nature.com

or

References

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

    Article CAS PubMed Google Scholar

  2. 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.

    CAS PubMed Google Scholar

  3. 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.

    Article CAS PubMed Google Scholar

  4. 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.

    CAS PubMed Google Scholar

  5. 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.

    CAS PubMed Google Scholar

  6. 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.

    Article CAS PubMed PubMed Central Google Scholar

  7. 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.

    CAS PubMed Google Scholar

  8. 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.

    Article CAS PubMed Google Scholar

  9. 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.

    Article CAS PubMed Google Scholar

  10. 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.

    Article CAS PubMed Google Scholar

  11. 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.

    Article CAS PubMed Google Scholar

  12. 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.

    CAS PubMed Google Scholar

  13. 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.

    CAS PubMed Google Scholar

  14. 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.

    Article CAS PubMed Google Scholar

  15. 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.

    CAS PubMed Google Scholar

  16. 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.

    Article CAS PubMed PubMed Central Google Scholar

  17. 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.

    Article CAS PubMed Google Scholar

  18. 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.

    CAS PubMed Google Scholar

  19. 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.

    CAS PubMed Google Scholar

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

    Article CAS PubMed Google Scholar

  21. 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.

    Article CAS PubMed PubMed Central Google Scholar

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

    Article CAS PubMed Google Scholar

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

    Article CAS PubMed Google Scholar

  24. 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.

    Article CAS PubMed Google Scholar

  25. 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.

    Article CAS PubMed Google Scholar

  26. 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.

    Article CAS PubMed Google Scholar

  27. 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.

    Article CAS PubMed Google Scholar

  28. 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.

    Article CAS PubMed Google Scholar

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

    Article CAS PubMed Google Scholar

  30. 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.

    Article CAS PubMed Google Scholar

  31. 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.

    Article CAS PubMed PubMed Central Google Scholar

  32. 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.

    Article CAS PubMed PubMed Central Google Scholar

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

    Article CAS PubMed Google Scholar

  34. 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.

    Article CAS PubMed PubMed Central Google Scholar

  35. 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.

    Article CAS PubMed PubMed Central Google Scholar

  36. 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.

    Article CAS PubMed PubMed Central Google Scholar

  37. 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.

    Article CAS PubMed Google Scholar

  38. 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.

    Article CAS PubMed Google Scholar

  39. 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.

    Article CAS PubMed Google Scholar

  40. 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.

    Article CAS PubMed Google Scholar

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

    Article CAS PubMed Google Scholar

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

    Article CAS PubMed Google Scholar

  43. 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.

    CAS PubMed Google Scholar

  44. 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.

    CAS PubMed Google Scholar

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

    Article CAS PubMed Google Scholar

  46. 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.

    Article CAS PubMed Google Scholar

  47. 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.

    Article CAS PubMed PubMed Central Google Scholar

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

    Article CAS PubMed Google Scholar

  49. 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.

    Article CAS PubMed Google Scholar

  50. 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.

    Article CAS PubMed Google Scholar

  51. 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.

    Article CAS PubMed Google Scholar

  52. 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.

    Article CAS PubMed Google Scholar

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

    Article CAS PubMed Google Scholar

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

    Article CAS PubMed PubMed Central Google Scholar

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

    Article CAS Google Scholar

  56. 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.

    Article CAS PubMed Google Scholar

  57. 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.

    Article CAS PubMed PubMed Central Google Scholar

  58. 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.

    Article CAS PubMed Google Scholar

  59. 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.

    Article CAS PubMed PubMed Central Google Scholar

  60. 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.

    CAS PubMed Google Scholar

  61. 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.

    Article CAS PubMed Google Scholar

  62. 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.

    Article CAS PubMed Google Scholar

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

    Article CAS PubMed Google Scholar

  64. 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.

    CAS PubMed Google Scholar

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

    Article CAS PubMed PubMed Central Google Scholar

  66. 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.

    Article CAS PubMed Google Scholar

  67. 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.

    Article CAS PubMed Google Scholar

  68. 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.

    Article CAS PubMed Google Scholar

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

    Article CAS PubMed Google Scholar

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

    Article CAS PubMed Google Scholar

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

    CAS Google Scholar

  72. 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.

    Article CAS PubMed Google Scholar

  73. 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.

    Article CAS PubMed Google Scholar

  74. 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.

    Article CAS Google Scholar

  75. 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.

    Article CAS PubMed Google Scholar

  76. 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.

    Article CAS PubMed Google Scholar

  77. 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.

    Article CAS PubMed Google Scholar

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

    Article CAS PubMed Google Scholar

  79. 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.

    Article CAS PubMed PubMed Central Google Scholar

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

    Article CAS PubMed Google Scholar

  81. 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.

    Article CAS PubMed PubMed Central Google Scholar

  82. 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.

    Article CAS PubMed PubMed Central Google Scholar

  83. 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.

    Article CAS PubMed Google Scholar

Download references

Acknowledgements

Work in the DeBose-Boyd laboratory is supported by grants from the National Institutes of Health (HL20948), the Perot Family Foundation, the American Heart Association (0540128N), and the W.M. Keck Foundation.

Author information

Authors and Affiliations

  1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, 75390-9046, TX, USA

    Russell A DeBose-Boyd

Authors
  1. Russell A DeBose-Boyd

Corresponding author

Correspondence to Russell A DeBose-Boyd.

About this article

Cite this article

DeBose-Boyd, R. Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res 18, 609–621 (2008). https://doi.org/10.1038/cr.2008.61

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/cr.2008.61

Keywords

Search

Advanced search

Quick links

AltStyle によって変換されたページ (->オリジナル) /