1932

Abstract

The polytopic, endoplasmic reticulum (ER) membrane protein 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase produces mevalonate, the key intermediate in the synthesis of cholesterol and many nonsterol isoprenoids including geranylgeranyl pyrophosphate (GGpp). Transcriptional, translational, and posttranslational feedback mechanisms converge on this reductase to ensure cells maintain a sufficient supply of essential nonsterol isoprenoids but avoid overaccumulation of cholesterol and other sterols. The focus of this review is mechanisms for the posttranslational regulation of HMG CoA reductase, which include sterol-accelerated ubiquitination and ER-associated degradation (ERAD) that is augmented by GGpp. We discuss how GGpp-induced ER-to-Golgi trafficking of the vitamin K synthetic enzyme UbiA prenyltransferase domain–containing protein-1 (UBIAD1) modulates HMG CoA reductase ERAD to balance the synthesis of sterol and nonsterol isoprenoids. We also summarize the characterization of genetically manipulated mice, which established that sterol-accelerated, UBIAD1-modulated ERAD plays a major role in regulation of HMG CoA reductase and cholesterol metabolism in vivo.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-081820-101010
2021-06-20
2024-04-23
Loading full text...

Full text loading...

/deliver/fulltext/biochem/90/1/annurev-biochem-081820-101010.html?itemId=/content/journals/10.1146/annurev-biochem-081820-101010&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Schoenheimer R, Breusch F. 1933. Synthesis and destruction of cholesterol in the organism. J. Biol. Chem. 103:439–48
    [Google Scholar]
  2. 2. 
    Gould RG, Taylor CB, Hagerman JS, Warner I, Campbell DJ 1953. Cholesterol metabolism. I. Effect of dietary cholesterol on the synthesis of cholesterol in dog tissue in vitro. J. Biol. Chem. 201:519–28
    [Google Scholar]
  3. 3. 
    Bloch K. 1965. The biological synthesis of cholesterol. Science 150:19–28
    [Google Scholar]
  4. 4. 
    Siperstein MD, Guest MJ. 1960. Studies on the site of the feedback control of cholesterol synthesis. J. Clin. Investig. 39:642–52
    [Google Scholar]
  5. 5. 
    Siperstein MD, Fagan VM. 1966. Feedback control of mevalonate synthesis by dietary cholesterol. J. Biol. Chem. 241:602–9
    [Google Scholar]
  6. 6. 
    Bucher NL, Overath P, Lynen F. 1960. β-Hydroxy-β-methyl-glutaryl coenzyme A reductase, cleavage and condensing enzymes in relation to cholesterol formation in rat liver. Biochim. Biophys. Acta 40:491–501
    [Google Scholar]
  7. 7. 
    Gould RG, Swyryd EA. 1966. Sites of control of hepatic cholesterol biosynthesis. J. Lipid Res. 7:698–707
    [Google Scholar]
  8. 8. 
    Gaylor JL. 2002. Membrane-bound enzymes of cholesterol synthesis from lanosterol. Biochem. Biophys. Res. Commun. 292:1139–46
    [Google Scholar]
  9. 9. 
    Edwards PA, Ericsson J. 1999. Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway. Annu. Rev. Biochem. 68:157–85
    [Google Scholar]
  10. 10. 
    Qi X, Li X. 2020. Mechanistic insights into the generation and transduction of Hedgehog signaling. Trends Biochem. Sci. 45:397–410
    [Google Scholar]
  11. 11. 
    Hu A, Song BL. 2019. The interplay of Patched, Smoothened and cholesterol in Hedgehog signaling. Curr. Opin. Cell Biol. 61:31–38
    [Google Scholar]
  12. 12. 
    Wang M, Casey PJ. 2016. Protein prenylation: Unique fats make their mark on biology. Nat. Rev. Mol. Cell Biol. 17:110–22
    [Google Scholar]
  13. 13. 
    Stossel TP. 2008. The discovery of statins. Cell 134:903–5
    [Google Scholar]
  14. 14. 
    Brown MS, Goldstein JL. 1980. Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. J. Lipid Res. 21:505–17
    [Google Scholar]
  15. 15. 
    Goldstein JL, Brown MS. 1990. Regulation of the mevalonate pathway. Nature 343:425–30
    [Google Scholar]
  16. 16. 
    Horton JD, Goldstein JL, Brown MS. 2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Investig. 109:1125–31
    [Google Scholar]
  17. 17. 
    Brown MS, Radhakrishnan A, Goldstein JL. 2018. Retrospective on cholesterol homeostasis: the central role of Scap. Annu. Rev. Biochem. 87:783–807
    [Google Scholar]
  18. 18. 
    Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y et al. 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
    [Google Scholar]
  19. 19. 
    Yabe D, Brown MS, Goldstein JL 2002. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element–binding proteins. PNAS 99:12753–58
    [Google Scholar]
  20. 20. 
    Radhakrishnan A, Goldstein JL, McDonald JG, Brown MS. 2008. Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance. Cell Metab 8:512–21
    [Google Scholar]
  21. 21. 
    Radhakrishnan A, Sun LP, Kwon HJ, Brown MS, Goldstein JL. 2004. Direct binding of cholesterol to the purified membrane region of SCAP; mechanism for a sterol-sensing domain. Mol. Cell 15:259–68
    [Google Scholar]
  22. 22. 
    Nakanishi M, Goldstein JL, 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. 263:8929–37
    [Google Scholar]
  23. 23. 
    Chin DJ, Gil G, Russell DW, Liscum L, Luskey KL et al. 1984. Nucleotide sequence of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase, a glycoprotein of endoplasmic reticulum. Nature 308:613–17
    [Google Scholar]
  24. 24. 
    Roitelman J, Olender EH, Bar-Nun S, Dunn WA Jr., 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. 117:959–73
    [Google Scholar]
  25. 25. 
    Liscum L, Finer-Moore J, Stroud RM, Luskey KL, Brown MS, Goldstein JL. 1985. Domain structure of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a glycoprotein of the endoplasmic reticulum. J. Biol. Chem. 260:522–30
    [Google Scholar]
  26. 26. 
    Gil G, Faust JR, Chin DJ, Goldstein JL, Brown MS. 1985. Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzyme. Cell 41:249–58
    [Google Scholar]
  27. 27. 
    Skalnik DG, Narita H, Kent C, Simoni RD. 1988. The membrane domain of 3-hydroxy-3-methylglutaryl-coenzyme A reductase confers endoplasmic reticulum localization and sterol-regulated degradation onto β-galactosidase. J. Biol. Chem. 263:6836–41
    [Google Scholar]
  28. 28. 
    Inoue S, Bar-Nun S, Roitelman J, Simoni RD. 1991. Inhibition of degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo by cysteine protease inhibitors. J. Biol. Chem. 266:13311–17
    [Google Scholar]
  29. 29. 
    Ravid T, Doolman R, Avner R, Harats D, Roitelman J. 2000. The ubiquitin-proteasome pathway mediates the regulated degradation of mammalian 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J. Biol. Chem. 275:35840–47
    [Google Scholar]
  30. 30. 
    Hua X, Nohturfft A, Goldstein JL, Brown MS. 1996. Sterol resistance in CHO cells traced to point mutation in SREBP cleavage-activating protein. Cell 87:415–26
    [Google Scholar]
  31. 31. 
    Nohturfft A, Brown MS, Goldstein JL. 1998. Topology of SREBP cleavage-activating protein, a polytopic membrane protein with a sterol-sensing domain. J. Biol. Chem. 273:17243–50
    [Google Scholar]
  32. 32. 
    Sakai J, Nohturfft A, Cheng D, Ho YK, Brown MS, 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. 272:20213–21
    [Google Scholar]
  33. 33. 
    Sakai J, Nohturfft A, Goldstein JL, Brown MS. 1998. Cleavage of sterol regulatory element-binding proteins (SREBPs) at site-1 requires interaction with SREBP cleavage-activating protein. Evidence from in vivo competition studies. J. Biol. Chem. 273:5785–93
    [Google Scholar]
  34. 34. 
    Sever N, Yang T, Brown MS, Goldstein JL, DeBose-Boyd RA. 2003. Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Mol. Cell 11:25–33
    [Google Scholar]
  35. 35. 
    Sever N, Song BL, Yabe D, Goldstein JL, Brown MS, DeBose-Boyd RA. 2003. Insig-dependent ubiquitination and degradation of mammalian 3-hydroxy-3-methylglutaryl-CoA reductase stimulated by sterols and geranylgeraniol. J. Biol. Chem. 278:52479–90
    [Google Scholar]
  36. 36. 
    Song BL, Sever N, DeBose-Boyd RA. 2005. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol. Cell 19:829–40
    [Google Scholar]
  37. 37. 
    Jo Y, Lee PC, Sguigna PV, DeBose-Boyd RA 2011. Sterol-induced degradation of HMG CoA reductase depends on interplay of two Insigs and two ubiquitin ligases, gp78 and Trc8. PNAS 108:20503–8
    [Google Scholar]
  38. 38. 
    Jiang LY, Jiang W, Tian N, Xiong YN, Liu J et al. 2018. Ring finger protein 145 (RNF145) is a ubiquitin ligase for sterol-induced degradation of HMG-CoA reductase. J. Biol. Chem. 293:4047–55
    [Google Scholar]
  39. 39. 
    Endo A, Kuroda M, Tanzawa K. 1976. Competitive inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by ML-236A and ML-236B fungal metabolites, having hypocholesterolemic activity. FEBS Lett 72:323–26
    [Google Scholar]
  40. 40. 
    Brown MS, Faust JR, 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. 253:1121–28
    [Google Scholar]
  41. 41. 
    Correll CC, Edwards PA. 1994. Mevalonic acid-dependent degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo and in vitro. J. Biol. Chem. 269:633–38
    [Google Scholar]
  42. 42. 
    Roitelman J, Simoni RD. 1992. Distinct sterol and nonsterol signals for the regulated degradation of 3-hydroxy-3-methylglutaryl-CoA reductase. J. Biol. Chem. 267:25264–73
    [Google Scholar]
  43. 43. 
    Hampton RY, Gardner RG, Rine J. 1996. 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 7:2029–44
    [Google Scholar]
  44. 44. 
    Wangeline MA, Vashistha N, Hampton RY. 2017. Proteostatic tactics in the strategy of sterol regulation. Annu. Rev. Cell Dev. Biol. 33:467–89
    [Google Scholar]
  45. 45. 
    Hampton RY, Koning A, Wright R, Rine J 1996. In vivo examination of membrane protein localization and degradation with green fluorescent protein. PNAS 93:828–33
    [Google Scholar]
  46. 46. 
    Wangeline MA, Hampton RY. 2018.. “ Mallostery”-ligand-dependent protein misfolding enables physiological regulation by ERAD. J. Biol. Chem. 293:14937–50
    [Google Scholar]
  47. 47. 
    Garza RM, Tran PN, Hampton RY. 2009. Geranylgeranyl pyrophosphate is a potent regulator of HRD-dependent 3-hydroxy-3-methylglutaryl-CoA reductase degradation in yeast. J. Biol. Chem. 284:35368–80
    [Google Scholar]
  48. 48. 
    Morris LL, Hartman IZ, Jun DJ, Seemann J, DeBose-Boyd RA. 2014. Sequential actions of the AAA-ATPase valosin-containing protein (VCP)/p97 and the proteasome 19 S regulatory particle in sterol-accelerated, endoplasmic reticulum (ER)-associated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J. Biol. Chem. 289:19053–66
    [Google Scholar]
  49. 49. 
    Hartman IZ, Liu P, Zehmer JK, Luby-Phelps K, Jo Y et al. 2010. 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. 285:19288–98
    [Google Scholar]
  50. 50. 
    Bodnar NO, Kim KH, Ji Z, Wales TE, Svetlov V et al. 2018. Structure of the Cdc48 ATPase with its ubiquitin-binding cofactor Ufd1-Npl4. Nat. Struct. Mol. Biol. 25:616–22
    [Google Scholar]
  51. 51. 
    Bodnar N, Rapoport T. 2017. Toward an understanding of the Cdc48/p97 ATPase. F1000Res 6:1318
    [Google Scholar]
  52. 52. 
    Bodnar NO, Rapoport TA. 2017. Molecular mechanism of substrate processing by the Cdc48 ATPase complex. Cell 169:722–35.e9
    [Google Scholar]
  53. 53. 
    Ehlinger A, Walters KJ. 2013. Structural insights into proteasome activation by the 19S regulatory particle. Biochemistry 52:3618–28
    [Google Scholar]
  54. 54. 
    Crick DC, Andres DA, Waechter CJ. 1997. Novel salvage pathway utilizing farnesol and geranylgeraniol for protein isoprenylation. Biochem. Biophys. Res. Commun. 237:483–87
    [Google Scholar]
  55. 55. 
    Schumacher MM, Elsabrouty R, Seemann J, Jo Y, DeBose-Boyd RA. 2015. The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase. eLife 4:e05560
    [Google Scholar]
  56. 56. 
    Roux KJ, Kim DI, Raida M, Burke B. 2012. A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. J. Cell Biol. 196:801–10
    [Google Scholar]
  57. 57. 
    McGarvey TW, Nguyen T, Puthiyaveettil R, Tomaszewski JE, Malkowicz SB. 2003. TERE1, a novel gene affecting growth regulation in prostate carcinoma. Prostate 54:144–55
    [Google Scholar]
  58. 58. 
    McGarvey TW, Nguyen T, Tomaszewski JE, Monson FC, Malkowicz SB. 2001. Isolation and characterization of the TERE1 gene, a gene down-regulated in transitional cell carcinoma of the bladder. Oncogene 20:1042–51
    [Google Scholar]
  59. 59. 
    Li W. 2016. Bringing bioactive compounds into membranes: the UbiA superfamily of intramembrane aromatic prenyltransferases. Trends Biochem. Sci. 41:356–70
    [Google Scholar]
  60. 60. 
    Nakagawa K, Hirota Y, Sawada N, Yuge N, Watanabe M et al. 2010. Identification of UBIAD1 as a novel human menaquinone-4 biosynthetic enzyme. Nature 468:117–21
    [Google Scholar]
  61. 61. 
    Hirota Y, Tsugawa N, Nakagawa K, Suhara Y, Tanaka K et al. 2013. Menadione (vitamin K3) is a catabolic product of oral phylloquinone (vitamin K1) in the intestine and a circulating precursor of tissue menaquinone-4 (vitamin K2) in rats. J. Biol. Chem. 288:33071–80
    [Google Scholar]
  62. 62. 
    Orr A, Dube MP, Marcadier J, Jiang H, Federico A et al. 2007. Mutations in the UBIAD1 gene, encoding a potential prenyltransferase, are causal for Schnyder crystalline corneal dystrophy. PLOS ONE 2:e685
    [Google Scholar]
  63. 63. 
    Weiss JS, Kruth HS, Kuivaniemi H, Tromp G, White PS et al. 2007. Mutations in the UBIAD1 gene on chromosome short arm 1, region 36, cause Schnyder crystalline corneal dystrophy. Investig. Ophthalmol. Vis. Sci. 48:5007–12
    [Google Scholar]
  64. 64. 
    Weiss JS. 2007. Visual morbidity in thirty-four families with Schnyder crystalline corneal dystrophy (an American Ophthalmological Society thesis). Trans. Am. Ophthalmol. Soc. 105:616–48
    [Google Scholar]
  65. 65. 
    McCarthy M, Innis S, Dubord P, White V. 1994. Panstromal Schnyder corneal dystrophy. A clinical pathologic report with quantitative analysis of corneal lipid composition. Ophthalmology 101:895–901
    [Google Scholar]
  66. 66. 
    Gaynor PM, Zhang WY, Weiss JS, Skarlatos SI, Rodrigues MM, Kruth HS. 1996. Accumulation of HDL apolipoproteins accompanies abnormal cholesterol accumulation in Schnyder's corneal dystrophy. Arterioscler. Thromb. Vasc. Biol. 16:992–99
    [Google Scholar]
  67. 67. 
    Yamada M, Mochizuki H, Kamata Y, Nakamura Y, Mashima Y. 1998. Quantitative analysis of lipid deposits from Schnyder's corneal dystrophy. Br. J. Ophthalmol. 82:444–47
    [Google Scholar]
  68. 68. 
    Thiel HJ, Voigt GJ, Parwaresch MR. 1977.. [ Crystalline corneal dystrophy (Schnyder) in the presence of familial type IIa hyperlipoproteinaemia. ]. Klin. Monbl. Augenheilkd. 171:678–84
    [Google Scholar]
  69. 69. 
    Brownstein S, Jackson WB, Onerheim RM. 1991. Schnyder's crystalline corneal dystrophy in association with hyperlipoproteinemia: histopathological and ultrastructural findings. Can. J. Ophthalmol. 26:273–79
    [Google Scholar]
  70. 70. 
    Crispin S. 2002. Ocular lipid deposition and hyperlipoproteinaemia. Prog. Retin. Eye Res. 21:169–224
    [Google Scholar]
  71. 71. 
    Nickerson ML, Bosley AD, Weiss JS, Kostiha BN, Hirota Y et al. 2013. The UBIAD1 prenyltransferase links menaquinone-4 synthesis to cholesterol metabolic enzymes. Hum. Mutat. 34:317–29 Erratum. Hum.Mutat. 34:1046
    [Google Scholar]
  72. 72. 
    Nowinska AK, Wylegala E, Teper S, Lyssek-Boron A, Aragona P et al. 2014. Phenotype-genotype correlation in patients with Schnyder corneal dystrophy. Cornea 33:497–503
    [Google Scholar]
  73. 73. 
    Lin BR, Frausto RF, Vo RC, Chiu SY, Chen JL, Aldave AJ. 2016. Identification of the first de novo UBIAD1 gene mutation associated with Schnyder corneal dystrophy. J. Ophthalmol. 2016.1968493
    [Google Scholar]
  74. 74. 
    Huang H, Levin EJ, Liu S, Bai Y, Lockless SW, Zhou M. 2014. Structure of a membrane-embedded prenyltransferase homologous to UBIAD1. PLOS Biol 12:e1001911
    [Google Scholar]
  75. 75. 
    Cheng W, Li W. 2014. Structural insights into ubiquinone biosynthesis in membranes. Science 343:878–81
    [Google Scholar]
  76. 76. 
    Hirota Y, Nakagawa K, Sawada N, Okuda N, Suhara Y et al. 2015. Functional characterization of the vitamin K2 biosynthetic enzyme UBIAD1. PLOS ONE 10:e0125737
    [Google Scholar]
  77. 77. 
    Jun DJ, Schumacher MM, Hwang S, Kinch LN, Grishin NV, DeBose-Boyd RA. 2020. Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation. J. Lipid Res. 61:746–57
    [Google Scholar]
  78. 78. 
    Schumacher MM, Jun DJ, Jo Y, Seemann J, DeBose-Boyd RA. 2016. Geranylgeranyl-regulated transport of the prenyltransferase UBIAD1 between membranes of the ER and Golgi. J. Lipid Res. 57:1286–99
    [Google Scholar]
  79. 79. 
    Schrödinger LLC. 2018. The PyMOL Molecular Graphics System, Version 2.0. Molecular Visualization Software https://pymol.org/
    [Google Scholar]
  80. 80. 
    Nickerson ML, Kostiha BN, Brandt W, Fredericks W, Xu KP et al. 2010. UBIAD1 mutation alters a mitochondrial prenyltransferase to cause Schnyder corneal dystrophy. PLOS ONE 5:e10760
    [Google Scholar]
  81. 81. 
    Mugoni V, Postel R, Catanzaro V, De Luca E, Turco E et al. 2013. Ubiad1 is an antioxidant enzyme that regulates eNOS activity by CoQ10 synthesis. Cell 152:504–18
    [Google Scholar]
  82. 82. 
    Wang X, Wang D, Jing P, Wu Y, Xia Y et al. 2013. A novel Golgi retention signal RPWS for tumor suppressor UBIAD1. PLOS ONE 8:e72015
    [Google Scholar]
  83. 83. 
    Zanetti G, Pahuja KB, Studer S, Shim S, Schekman R. 2012. COPII and the regulation of protein sorting in mammals. Nat. Cell Biol. 14:20–28
    [Google Scholar]
  84. 84. 
    Barlowe CK, Miller EA. 2013. Secretory protein biogenesis and traffic in the early secretory pathway. Genetics 193:383–410
    [Google Scholar]
  85. 85. 
    Aridor M, Weissman J, Bannykh S, Nuoffer C, Balch WE. 1998. Cargo selection by the COPII budding machinery during export from the ER. J. Cell Biol. 141:61–70
    [Google Scholar]
  86. 86. 
    Rexach MF, Schekman RW. 1991. Distinct biochemical requirements for the budding, targeting, and fusion of ER-derived transport vesicles. J. Cell Biol. 114:219–29
    [Google Scholar]
  87. 87. 
    Rowe T, Aridor M, McCaffery JM, Plutner H, Nuoffer C, Balch WE. 1996. COPII vesicles derived from mammalian endoplasmic reticulum microsomes recruit COPI. J. Cell Biol. 135:895–911
    [Google Scholar]
  88. 88. 
    Storrie B, White J, Rottger S, Stelzer EH, Suganuma T, Nilsson T. 1998. Recycling of Golgi-resident glycosyltransferases through the ER reveals a novel pathway and provides an explanation for nocodazole-induced Golgi scattering. J. Cell Biol. 143:1505–21
    [Google Scholar]
  89. 89. 
    Sengupta P, Satpute-Krishnan P, Seo AY, Burnette DT, Patterson GH, Lippincott-Schwartz J 2015. ER trapping reveals Golgi enzymes continually revisit the ER through a recycling pathway that controls Golgi organization. PNAS 112:E6752–61
    [Google Scholar]
  90. 90. 
    D'Arcangelo JG, Stahmer KR, Miller EA. 2013. Vesicle-mediated export from the ER: COPII coat function and regulation. Biochim. Biophys. Acta Mol. Cell Res. 1833:2464–72
    [Google Scholar]
  91. 91. 
    Kita T, Brown MS, 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. Investig. 66:1094–100
    [Google Scholar]
  92. 92. 
    Engelking LJ, Liang G, Hammer RE, Takaishi K, Kuriyama H et al. 2005. Schoenheimer effect explained—feedback regulation of cholesterol synthesis in mice mediated by Insig proteins. J. Clin. Investig. 115:2489–98
    [Google Scholar]
  93. 93. 
    Hwang S, Hartman IZ, Calhoun LN, Garland K, Young GA et al. 2016. Contribution of accelerated degradation to feedback regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol metabolism in the liver. J. Biol. Chem. 291:13479–94
    [Google Scholar]
  94. 94. 
    Jo Y, Hamilton JS, Hwang S, Garland K, Smith GA et al. 2019. Schnyder corneal dystrophy-associated UBIAD1 inhibits ER-associated degradation of HMG CoA reductase in mice. eLife 8:e44396
    [Google Scholar]
  95. 95. 
    Doolman R, Leichner GS, Avner R, Roitelman J. 2004. Ubiquitin is conjugated by membrane ubiquitin ligase to three sites, including the N terminus, in transmembrane region of mammalian 3-hydroxy-3-methylglutaryl coenzyme A reductase: implications for sterol-regulated enzyme degradation. J. Biol. Chem. 279:38184–93
    [Google Scholar]
  96. 96. 
    Shearer MJ, Newman P. 2014. Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. J. Lipid Res. 55:345–62
    [Google Scholar]
  97. 97. 
    Shearer MJ, Okano T. 2018. Key pathways and regulators of vitamin K function and intermediary metabolism. Annu. Rev. Nutr. 38:127–51
    [Google Scholar]
  98. 98. 
    Booth SL. 2009. Roles for vitamin K beyond coagulation. Annu. Rev. Nutr. 29:89–110
    [Google Scholar]
  99. 99. 
    Nakagawa K, Sawada N, Hirota Y, Uchino Y, Suhara Y et al. 2014. Vitamin K2 biosynthetic enzyme, UBIAD1 is essential for embryonic development of mice. PLOS ONE 9:e104078
    [Google Scholar]
  100. 100. 
    Schumacher MM, Jun DJ, Johnson BM, DeBose-Boyd RA. 2018. UbiA prenyltransferase domain–containing protein-1 modulates HMG-CoA reductase degradation to coordinate synthesis of sterol and nonsterol isoprenoids. J. Biol. Chem. 293:312–23
    [Google Scholar]
  101. 101. 
    Ohashi K, Osuga J, Tozawa R, Kitamine T, Yagyu H et al. 2003. Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene. J. Biol. Chem. 278:42936–41
    [Google Scholar]
  102. 102. 
    Jo Y, Kim SS, Garland K, Fuentes I, DiCarlo LM et al. 2020. Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated with Ubiad1 deficiency. eLife 9:e54841
    [Google Scholar]
  103. 103. 
    Buitenhuis HC, Soute BA, Vermeer C. 1990. Comparison of the vitamins K1, K2 and K3 as cofactors for the hepatic vitamin K-dependent carboxylase. Biochim. Biophys. Acta Gen. Subj. 1034:170–75
    [Google Scholar]
  104. 104. 
    Radhakrishnan A, Ikeda Y, Kwon HJ, Brown MS, Goldstein JL 2007. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to Insig.. PNAS 104:6511–18
    [Google Scholar]
  105. 105. 
    Song BL, Javitt NB, DeBose-Boyd RA. 2005. Insig-mediated degradation of HMG CoA reductase stimulated by lanosterol, an intermediate in the synthesis of cholesterol. Cell Metab 1:179–89
    [Google Scholar]
  106. 106. 
    Sever N, Lee PC, Song BL, Rawson RB, 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. 279:43136–47
    [Google Scholar]
  107. 107. 
    Song BL, DeBose-Boyd RA. 2006. Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase stimulated by δ- and γ-tocotrienols. J. Biol. Chem. 281:25054–61
    [Google Scholar]
  108. 108. 
    Sun LP, Li L, Goldstein JL, Brown MS. 2005. Insig required for sterol-mediated inhibition of Scap/SREBP binding to COPII proteins in vitro. J. Biol. Chem. 280:26483–90
    [Google Scholar]
  109. 109. 
    Reihner E, Rudling M, Stahlberg D, Berglund L, Ewerth S et al. 1990. Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol. N. Engl. J. Med. 323:224–28
    [Google Scholar]
  110. 110. 
    Schonewille M, de Boer JF, Mele L, Wolters H, Bloks VW et al. 2016. Statins increase hepatic cholesterol synthesis and stimulate fecal cholesterol elimination in mice. J. Lipid Res. 57:1455–64
    [Google Scholar]
  111. 111. 
    Goldberg IJ, Holleran S, Ramakrishnan R, Adams M, Palmer RH et al. 1990. Lack of effect of lovastatin therapy on the parameters of whole-body cholesterol metabolism. J. Clin. Investig. 86:801–8
    [Google Scholar]
  112. 112. 
    Engelking LJ, Evers BM, Richardson JA, Goldstein JL, Brown MS, Liang G. 2006. Severe facial clefting in Insig-deficient mouse embryos caused by sterol accumulation and reversed by lovastatin. J. Clin. Investig. 116:2356–65
    [Google Scholar]
  113. 113. 
    Kunwar PS, Siekhaus DE, Lehmann R. 2006. In vivo migration: a germ cell perspective. Annu. Rev. Cell Dev. Biol. 22:237–65
    [Google Scholar]
  114. 114. 
    Nakagawa K, Fujiwara K, Nishimura A, Murakami C, Kawamoto K et al. 2019. UBIAD1 plays an essential role in the survival of pancreatic acinar cells. Int. J. Mol. Sci. 20:1971
    [Google Scholar]
  115. 115. 
    Yeh YS, Jheng HF, Iwase M, Kim M, Mohri S et al. 2018. The mevalonate pathway is indispensable for adipocyte survival. iScience 9:175–91
    [Google Scholar]
  116. 116. 
    Tabb MM, Sun A, Zhou C, Grun F, Errandi J et al. 2003. Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR. J. Biol. Chem. 278:43919–27
    [Google Scholar]
  117. 117. 
    Azuma K, Casey SC, Ito M, Urano T, Horie K et al. 2010. Pregnane X receptor knockout mice display osteopenia with reduced bone formation and enhanced bone resorption. J. Endocrinol. 207:257–63
    [Google Scholar]
  118. 118. 
    Thompson PD, Clarkson P, Karas RH. 2003. Statin-associated myopathy. JAMA 289:1681–90
    [Google Scholar]
  119. 119. 
    Ward NC, Watts GF, Eckel RH. 2019. Statin toxicity. Circ Res 124:328–50
    [Google Scholar]
  120. 120. 
    Osaki Y, Nakagawa Y, Miyahara S, Iwasaki H, Ishii A et al. 2015. Skeletal muscle-specific HMG-CoA reductase knockout mice exhibit rhabdomyolysis: a model for statin-induced myopathy. Biochem. Biophys. Res. Commun. 466:536–40
    [Google Scholar]
  121. 121. 
    Harshman SG, Fu X, Karl JP, Barger K, Lamon-Fava S et al. 2016. Tissue concentrations of vitamin K and expression of key enzymes of vitamin K metabolism are influenced by sex and diet but not housing in C57Bl6 mice. J. Nutr. 146:1521–27
    [Google Scholar]
  122. 122. 
    Okano T, Shimomura Y, Yamane M, Suhara Y, Kamao M et al. 2008. Conversion of phylloquinone (Vitamin K1) into menaquinone-4 (Vitamin K2) in mice: two possible routes for menaquinone-4 accumulation in cerebra of mice. J. Biol. Chem. 283:11270–79
    [Google Scholar]
/content/journals/10.1146/annurev-biochem-081820-101010
Loading
/content/journals/10.1146/annurev-biochem-081820-101010
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error