Diabetes Metab J.  2014 Jun;38(3):171-180. 10.4093/dmj.2014.38.3.171.

Ubiquitin Ligases in Cholesterol Metabolism

• Jiang W
• Song BL

• KMID: 2280686
• DOI: http://doi.org/10.4093/dmj.2014.38.3.171

Abstract

To maintain cholesterol homeostasis, the processes of cholesterol metabolism are regulated at multiple levels including transcription, translation, and enzymatic activity. Recently, the regulation of protein stability of some key players in cholesterol metabolism has been characterized. More and more ubiquitin ligases have been identified including gp78, Hrd1, TRC8, TEB4, Fbw7, and inducible degrader of low density lipoprotein receptor. Their working mechanisms and physiological functions are becoming revealed. Here, we summarize the structure, substrates and function of these ubiquitin ligases. Their potential application in drug discovery is also discussed.

Keyword

Cholesterol metabolism; Protein homeostasis; Ubiquitin ligases

MeSH Terms

Cholesterol*
Drug Discovery
Homeostasis
Ligases*
Metabolism*
Protein Stability
Receptors, LDL
Ubiquitin*
Cholesterol
Ligases
Receptors, LDL
Ubiquitin

Figure

• 

  Fig. 1 An illustration of cholesterol homeostasis in a typical mammalian cell. This diagram shows the cellular cholesterol metabolism contains at least four major routes: 1) the cholesterol de nove biosynthesis from acetyl-CoA in the endoplasmic reticulum (ER); 2) the low density lipoprotein (LDL) receptor-mediated endocytosis of LDL-derived cholesterol from plasma; 3) the efflux mediated by ABC family transporters such as ATP-binding cassette, sub-family A (ABC1), member 1 (ABCA1)/ATP-binding cassette, sub-family G (WHITE), member 1 (ABCG1) and the secretion mediated by apolipoprotein B (ApoB); and 4) cholesterol is esterified to cholesterol esters (CE) by acyl-coenzyme A:cholesterol acyltransferase (ACAT). See text for more details. HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA; HDL, high density lipoprotein; TEB4, also called Membrane-Associated RING Finger Protein 6 (MRCH60); SM, squalene monoxygnease; HMGCR, HMG-CoA reductase; gp78, glycoprotein 78; TRC8, translocation in renal carcinoma on chromosome 8 protein; MTP, microsomal triglyceride transfer protein; SREBP-2, sterol regulatory element binding protein 2; Fbw7, F-box and WD repeat domain containing 7; LDLR, LDL receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; Insig-1, insulin induced gene 1; IDOL, inducible degrader of LDLR; VLDL, very low density lipoprotein; LXR, liver X receptor.

Reference

1. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Annu Rev Biochem. 2003; 72:137–174.

2. Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev. 2004; 25:947–970.

3. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998; 67:425–479.

4. 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.

5. Cao J, Wang J, Qi W, Miao HH, Wang J, Ge L, DeBose-Boyd RA, Tang JJ, Li BL, Song BL. 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.

6. Watanabe H, Carmi P, Hogan V, Raz T, Silletti S, Nabi IR, Raz A. Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor. J Biol Chem. 1991; 266:13442–13448.

7. Fang S, Ferrone M, Yang C, Jensen JP, Tiwari S, Weissman AM. The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc Natl Acad Sci U S A. 2001; 98:14422–14427.

8. Liang JS, Kim T, Fang S, Yamaguchi J, Weissman AM, Fisher EA, Ginsberg HN. Overexpression of the tumor autocrine motility factor receptor Gp78, a ubiquitin protein ligase, results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in HepG2 cells. J Biol Chem. 2003; 278:23984–23988.

9. Gong Y, Lee JN, Lee PC, Goldstein JL, Brown MS, Ye J. 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.

10. Liu TF, Tang JJ, Li PS, Shen Y, Li JG, Miao HH, Li BL, Song BL. Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis. Cell Metab. 2012; 16:213–225.

11. DeBose-Boyd RA. Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res. 2008; 18:609–621.

12. 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.

13. 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 Metab. 2005; 1:179–189.

14. 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.

15. Sever N, Song BL, Yabe D, Goldstein JL, Brown MS, DeBose-Boyd RA. 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.

16. Jo Y, Hartman IZ, DeBose-Boyd RA. Ancient ubiquitous protein-1 mediates sterol-induced ubiquitination of 3-hydroxy-3-methylglutaryl CoA reductase in lipid droplet-associated endoplasmic reticulum membranes. Mol Biol Cell. 2013; 24:169–183.

17. Hartman IZ, Liu P, Zehmer JK, Luby-Phelps K, Jo Y, Anderson RG, DeBose-Boyd RA. Sterol-induced dislocation of 3-hydroxy-3-methylglutaryl coenzyme A reductase from endoplasmic reticulum membranes into the cytosol through a subcellular compartment resembling lipid droplets. J Biol Chem. 2010; 285:19288–19298.

18. Jo Y, Lee PC, Sguigna PV, DeBose-Boyd RA. Sterol-induced degradation of HMG CoA reductase depends on interplay of two Insigs and two ubiquitin ligases, gp78 and Trc8. Proc Natl Acad Sci U S A. 2011; 108:20503–20508.

19. Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS. 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.

20. 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 U S A. 2002; 99:12753–12758.

21. Lee JN, Ye J. Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1. J Biol Chem. 2004; 279:45257–45265.

22. 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.

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

24. Fisher EA, Khanna NA, McLeod RS. Ubiquitination regulates the assembly of VLDL in HepG2 cells and is the committing step of the apoB-100 ERAD pathway. J Lipid Res. 2011; 52:1170–1180.

25. St Pierre P, Nabi IR. The Gp78 ubiquitin ligase: probing endoplasmic reticulum complexity. Protoplasma. 2012; 249:Suppl 1. S11–S18.

26. Kikkert M, Doolman R, Dai M, Avner R, Hassink G, van Voorden S, Thanedar S, Roitelman J, Chau V, Wiertz E. Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum. J Biol Chem. 2004; 279:3525–3534.

27. Morito D, Hirao K, Oda Y, Hosokawa N, Tokunaga F, Cyr DM, Tanaka K, Iwai K, Nagata K. Gp78 cooperates with RMA1 in endoplasmic reticulum-associated degradation of CFTRDeltaF508. Mol Biol Cell. 2008; 19:1328–1336.

28. Bernardi KM, Williams JM, Kikkert M, van Voorden S, Wiertz EJ, Ye Y, Tsai B. The E3 ubiquitin ligases Hrd1 and gp78 bind to and promote cholera toxin retro-translocation. Mol Biol Cell. 2010; 21:140–151.

29. Hampton RY, Gardner RG, Rine J. Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. Mol Biol Cell. 1996; 7:2029–2044.

30. Lee JP, Brauweiler A, Rudolph M, Hooper JE, Drabkin HA, Gemmill RM. The TRC8 ubiquitin ligase is sterol regulated and interacts with lipid and protein biosynthetic pathways. Mol Cancer Res. 2010; 8:93–106.

31. Gemmill RM, West JD, Boldog F, Tanaka N, Robinson LJ, Smith DI, Li F, Drabkin HA. The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. Proc Natl Acad Sci U S A. 1998; 95:9572–9577.

32. Chang TY, Chang CC, Ohgami N, Yamauchi Y. Cholesterol sensing, trafficking, and esterification. Annu Rev Cell Dev Biol. 2006; 22:129–157.

33. Tsai YC, Leichner GS, Pearce MM, Wilson GL, Wojcikiewicz RJ, Roitelman J, Weissman AM. Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system. Mol Biol Cell. 2012; 23:4484–4494.

34. Hassink G, Kikkert M, van Voorden S, Lee SJ, Spaapen R, van Laar T, Coleman CS, Bartee E, Fruh K, Chau V, Wiertz E. TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum. Biochem J. 2005; 388(Pt 2):647–655.

35. Kreft SG, Wang L, Hochstrasser M. Membrane topology of the yeast endoplasmic reticulum-localized ubiquitin ligase Doa10 and comparison with its human ortholog TEB4 (MARCH-VI). J Biol Chem. 2006; 281:4646–4653.

36. Foresti O, Ruggiano A, Hannibal-Bach HK, Ejsing CS, Carvalho P. Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4. Elife. 2013; 2:e00953.

37. Belter A, Skupinska M, Giel-Pietraszuk M, Grabarkiewicz T, Rychlewski L, Barciszewski J. Squalene monooxygenase - a target for hypercholesterolemic therapy. Biol Chem. 2011; 392:1053–1075.

38. Gill S, Stevenson J, Kristiana I, Brown AJ. Cholesterol-dependent degradation of squalene monooxygenase, a control point in cholesterol synthesis beyond HMG-CoA reductase. Cell Metab. 2011; 13:260–273.

39. Zavacki AM, Arrojo E Drigo R, Freitas BC, Chung M, Harney JW, Egri P, Wittmann G, Fekete C, Gereben B, Bianco AC. The E3 ubiquitin ligase TEB4 mediates degradation of type 2 iodothyronine deiodinase. Mol Cell Biol. 2009; 29:5339–5347.

40. Cardozo T, Pagano M. The SCF ubiquitin ligase: insights into a molecular machine. Nat Rev Mol Cell Biol. 2004; 5:739–751.

41. Welcker M, Clurman BE. FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation. Nat Rev Cancer. 2008; 8:83–93.

42. Sundqvist A, Bengoechea-Alonso MT, Ye X, Lukiyanchuk V, Jin J, Harper JW, Ericsson J. Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7). Cell Metab. 2005; 1:379–391.

43. Bengoechea-Alonso MT, Ericsson J. The ubiquitin ligase Fbxw7 controls adipocyte differentiation by targeting C/EBPalpha for degradation. Proc Natl Acad Sci U S A. 2010; 107:11817–11822.

44. Inuzuka H, Shaik S, Onoyama I, Gao D, Tseng A, Maser RS, Zhai B, Wan L, Gutierrez A, Lau AW, Xiao Y, Christie AL, Aster J, Settleman J, Gygi SP, Kung AL, Look T, Nakayama KI, DePinho RA, Wei W. SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. Nature. 2011; 471:104–109.

45. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997; 89:331–340.

46. Hirano Y, Yoshida M, Shimizu M, Sato R. Direct demonstration of rapid degradation of nuclear sterol regulatory element-binding proteins by the ubiquitin-proteasome pathway. J Biol Chem. 2001; 276:36431–36437.

47. Giandomenico V, Simonsson M, Gronroos E, Ericsson J. Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors. Mol Cell Biol. 2003; 23:2587–2599.

48. Onoyama I, Suzuki A, Matsumoto A, Tomita K, Katagiri H, Oike Y, Nakayama K, Nakayama KI. Fbxw7 regulates lipid metabolism and cell fate decisions in the mouse liver. J Clin Invest. 2011; 121:342–354.

49. Jeon TI, Esquejo RM, Roqueta-Rivera M, Phelan PE, Moon YA, Govindarajan SS, Esau CC, Osborne TF. An SREBP-responsive microRNA operon contributes to a regulatory loop for intracellular lipid homeostasis. Cell Metab. 2013; 18:51–61.

50. Chishti AH, Kim AC, Marfatia SM, Lutchman M, Hanspal M, Jindal H, Liu SC, Low PS, Rouleau GA, Mohandas N, Chasis JA, Conboy JG, Gascard P, Takakuwa Y, Huang SC, Benz EJ Jr, Bretscher A, Fehon RG, Gusella JF, Ramesh V, Solomon F, Marchesi VT, Tsukita S, Tsukita S, Hoover KB. The FERM domain: a unique module involved in the linkage of cytoplasmic proteins to the membrane. Trends Biochem Sci. 1998; 23:281–282.

51. Olsson PA, Korhonen L, Mercer EA, Lindholm D. MIR is a novel ERM-like protein that interacts with myosin regulatory light chain and inhibits neurite outgrowth. J Biol Chem. 1999; 274:36288–36292.

52. Zelcer N, Hong C, Boyadjian R, Tontonoz P. LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor. Science. 2009; 325:100–104.

53. Zhang L, Fairall L, Goult BT, Calkin AC, Hong C, Millard CJ, Tontonoz P, Schwabe JW. The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor. Genes Dev. 2011; 25:1262–1274.

54. Goldstein JL, Brown MS. The LDL receptor. Arterioscler Thromb Vasc Biol. 2009; 29:431–438.

55. Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res. 2009; 50:Suppl. S172–S177.

56. Scotti E, Hong C, Yoshinaga Y, Tu Y, Hu Y, Zelcer N, Boyadjian R, de Jong PJ, Young SG, Fong LG, Tontonoz P. Targeted disruption of the idol gene alters cellular regulation of the low-density lipoprotein receptor by sterols and liver x receptor agonists. Mol Cell Biol. 2011; 31:1885–1893.

57. Calkin AC, Goult BT, Zhang L, Fairall L, Hong C, Schwabe JW, Tontonoz P. FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors. Proc Natl Acad Sci U S A. 2011; 108:20107–20112.

58. Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R. A genomic and functional inventory of deubiquitinating enzymes. Cell. 2005; 123:773–786.