The endoplasmic reticulum is the port of entry for proteins into the secretory pathway and the site of synthesis for several important lipids, including cholesterol, triacylglycerol, and phospholipids. Protein production within the endoplasmic reticulum is tightly regulated by a cohort of resident machinery that coordinates the folding, modification, and deployment of secreted and integral membrane proteins. Proteins failing to attain their native conformation are degraded through the endoplasmic reticulum–associated degradation (ERAD) pathway via a series of tightly coupled steps: substrate recognition, dislocation, and ubiquitin-dependent proteasomal destruction. The same ERAD machinery also controls the flux through various metabolic pathways by coupling the turnover of metabolic enzymes to the levels of key metabolites. We review the current understanding and biological significance of ERAD-mediated regulation of lipid metabolism in mammalian cells.


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Literature Cited

  1. Adams CM, Goldstein JL, Brown MS. 1.  2003. Cholesterol-induced conformational change in SCAP enhanced by Insig proteins and mimicked by cationic amphiphiles. PNAS 100:1910647–52 [Google Scholar]
  2. Akopian D, Shen K, Zhang X, Shan SO. 2.  2013. Signal recognition particle: an essential protein-targeting machine. Annu. Rev. Biochem. 82:693–721 [Google Scholar]
  3. Benoist F, Grand-Perret T. 3.  1997. Co-translational degradation of apolipoprotein B100 by the proteasome is prevented by microsomal triglyceride transfer protein. Synchronized translation studies on HepG2 cells treated with an inhibitor of microsomal triglyceride transfer protein. J. Biol. Chem. 272:3320435–42 [Google Scholar]
  4. Bernardi KM, Williams JM, Inoue T, Schultz A, Tsai B. 4.  2013. A deubiquitinase negatively regulates retro-translocation of non-ubiquitinated substrates. Mol. Biol. Cell 24:223545–56 [Google Scholar]
  5. Bernasconi R, Galli C, Calanca V, Nakajima T, Molinari M. 5.  2010. Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates. J. Cell Biol. 188:2223–35 [Google Scholar]
  6. Blom D, Hirsch C, Stern P, Tortorella D, Ploegh HL. 6.  2004. A glycosylated type I membrane protein becomes cytosolic when peptide: N-glycanase is compromised. EMBO J. 23:3650–58 [Google Scholar]
  7. Braakman I, Bulleid NJ. 7.  2011. Protein folding and modification in the mammalian endoplasmic reticulum. Annu. Rev. Biochem. 80:71–99 [Google Scholar]
  8. Braun S, Matuschewski K, Rape M, Thoms S, Jentsch S. 8.  2002. Role of the ubiquitin-selective CDC48UFD1/NPL4chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J. 21:4615–21 [Google Scholar]
  9. Brown AJ, Sun L, Feramisco JD, Brown MS, Goldstein JL. 9.  2002. Cholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Mol. Cell 10:2237–45 [Google Scholar]
  10. Brown S, Brunschede Y, Goldstein L. 10.  1975. Inactivation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in vitro: an adenine nucleotide-dependent reaction catalyzed by a factor in human fibroblasts. J. Biol. Chem. 250:72502–9 [Google Scholar]
  11. Brown S, Goldstein L, Dietschy M. 11.  1979. Active and inactive forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the liver of the rat: comparison with the rate of cholesterol synthesis in different physiological states. J. Biol. Chem. 254:125144–49 [Google Scholar]
  12. Butkinaree C, Guo L, Ramkhelawon B, Wanschel A, Brodsky JL. 12.  et al. 2014. A regulator of secretory vesicle size, Kelch-like protein 12, facilitates the secretion of apolipoprotein B100 and very-low-density lipoproteins—brief report. Arterioscler. Thromb. Vasc. Biol. 34:2251–54 [Google Scholar]
  13. Cao J, Wang J, Qi W, Miao HH, Wang J. 13.  et al. 2007. Ufd1 is a cofactor of gp78 and plays a key role in cholesterol metabolism by regulating the stability of HMG-CoA reductase. Cell Metab. 6:2115–28 [Google Scholar]
  14. Carvalho P, Goder V, Rapoport TA. 14.  2006. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126:2361–73 [Google Scholar]
  15. Carvalho P, Stanley AM, Rapoport TA. 15.  2010. Retrotranslocation of a misfolded luminal ER protein by the ubiquitin-ligase Hrd1p. Cell 143:4579–91 [Google Scholar]
  16. Chen CY, Malchus NS, Hehn B, Stelzer W, Avci D. 16.  et al. 2014. Signal peptide peptidase functions in ERAD to cleave the unfolded protein response regulator XBP1u. EMBO J. 33:212492–506 [Google Scholar]
  17. Choi K, Kim H, Kang H, Lee SY, Lee SJ. 17.  et al. 2014. Regulation of diacylglycerol acyltransferase 2 protein stability by gp78-associated endoplasmic-reticulum-associated degradation. FEBS J. 281:133048–60 [Google Scholar]
  18. Christianson JC, Olzmann JA, Shaler TA, Sowa ME, Bennett EJ. 18.  et al. 2012. Defining human ERAD networks through an integrative mapping strategy. Nat. Cell Biol. 14:193–105 [Google Scholar]
  19. Christianson JC, Shaler TA, Tyler RE, Kopito RR. 19.  2008. OS-9 and GRP94 deliver mutant α1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD. Nat. Cell Biol. 10:3272–82 [Google Scholar]
  20. Christianson JC, Ye Y. 20.  2014. Cleaning up in the endoplasmic reticulum: ubiquitin in charge. Nat. Struct. Mol. Biol. 21:4325–35 [Google Scholar]
  21. Churchward MA, Rogasevskaia T, Höfgen J, Bau J, Coorssen JR. 21.  2005. Cholesterol facilitates the native mechanism of Ca2+-triggered membrane fusion. J. Cell Sci. 118:4833–48 [Google Scholar]
  22. Coleman RA, Lewin TM, Muoio DM. 22.  2000. Physiological and nutritional regulation of enzymes of triacylglycerol synthesis. Annu. Rev. Nutr. 20:77–103 [Google Scholar]
  23. Cormier JH, Tamura T, Sunryd JC, Hebert DN. 23.  2009. EDEM1 recognition and delivery of misfolded proteins to the SEL1L-containing ERAD complex. Mol. Cell 34:5627–33 [Google Scholar]
  24. DeBose-Boyd RA. 24.  2008. Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res. 18:6609–21 [Google Scholar]
  25. DeLaBarre B, Brunger AT. 25.  2003. Complete structure of p97/valosin-containing protein reveals communication between nucleotide domains. Nat. Struct. Biol. 10:10856–63 [Google Scholar]
  26. DeLaBarre B, Christianson JC, Kopito RR, Brunger AT. 26.  2006. Central pore residues mediate the p97/VCP activity required for ERAD. Mol. Cell. 22:4451–62 [Google Scholar]
  27. Denic V, Dötsch V, Sinning I. 27.  2013. Endoplasmic reticulum targeting and insertion of tail-anchored membrane proteins by the GET pathway. Cold Spring Harb. Perspect. Biol. 5:8a013334 [Google Scholar]
  28. Dixon JL, Furukawa S, Ginsberg HN. 28.  1991. Oleate stimulates secretion of apolipoprotein B-containing lipoproteins from Hep G2 cells by inhibiting early intracellular degradation of apolipoprotein B. J. Biol. Chem. 266:85080–86 [Google Scholar]
  29. Elbaz Y, Schuldiner M. 29.  2011. Staying in touch: the molecular era of organelle contact sites. Trends Biochem. Sci. 36:11616–23 [Google Scholar]
  30. Ernst R, Claessen JH, Mueller B, Sanyal S, Spooner E. 30.  et al. 2011. Enzymatic blockade of the ubiquitin-proteasome pathway. PLOS Biol. 8:3e1000605 [Google Scholar]
  31. Ernst R, Mueller B, Ploegh HL, Schlieker C. 31.  2009. The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER. Mol. Cell. 36:128–38 [Google Scholar]
  32. Feng B, Yao PM, Li Y, Devlin CM, Zhang D. 32.  et al. 2003. The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages. Nat. Cell Biol. 5:9781–92 [Google Scholar]
  33. Fisher EA, Ginsberg HN. 33.  2002. Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins. J. Biol. Chem. 277:2017377–80 [Google Scholar]
  34. Fisher EA, Khanna NA, McLeod RS. 34.  2011. Ubiquitination regulates the assembly of VLDL in HepG2 cells and is the committing step of the apoB-100 ERAD pathway. J. Lipid Res. 52:61170–80 [Google Scholar]
  35. Fisher EA, Lapierre LR, Junkins RD, McLeod RS. 35.  2008. The AAA-ATPase p97 facilitates degradation of apolipoprotein B by the ubiquitin–proteasome pathway. J. Lipid Res. 49:102149–60 [Google Scholar]
  36. Fleig L, Bergbold N, Sahasrabudhe P, Geiger B, Kaltak L, Lemberg MK. 36.  2012. Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of membrane proteins. Mol. Cell 47:4558–69 [Google Scholar]
  37. Flowers MT, Ntambi JM. 37.  2008. Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism. Curr. Opin. Lipidol. 19:3248–56 [Google Scholar]
  38. Foresti O, Rodriguez-Vaello V, Funaya C, Carvalho P. 38.  2014. Quality control of inner nuclear membrane proteins by the Asi complex. Science 346:6210751–55 [Google Scholar]
  39. Foresti O, Ruggiano A, Hannibal-Bach HK, Ejsing CS, Carvalho P. 39.  2013. Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4. eLife 2e00953 [Google Scholar]
  40. Fujimori T, Kamiya Y, Nagata K, Kato K, Hosokawa N. 40.  2013. Endoplasmic reticulum lectin XTP3-B inhibits endoplasmic reticulum-associated degradation of a misfolded α1-antitrypsin variant. FEBS J. 280:61563–75 [Google Scholar]
  41. Geiger R, Andritschke D, Friebe S, Herzog F, Luisoni S. 41.  et al. 2011. Bap31 and Bip are essential for dislocation of SV40 from the endoplasmic reticulum to the cytosol. Nat. Cell Biol. 13:111305–14 [Google Scholar]
  42. Gelman MS, Kopito RR. 42.  2002. Rescuing protein conformation: prospects for pharmacological therapy in cystic fibrosis. J. Clin. Investig. 110:111591–97 [Google Scholar]
  43. Gil G, Faust JR, Chin DJ, Goldstein JL, Brown MS. 43.  1985. Membrane-bound domain of HMG CoA reductase is required for sterol-enhanced degradation of the enzyme. Cell 41:1249–58 [Google Scholar]
  44. Gill S, Stevenson J, Kristiana I, Brown AJ. 44.  2011. Cholesterol-dependent degradation of squalene monooxygenase, a control point in cholesterol synthesis beyond HMG-CoA reductase. Cell Metab. 13:3260–73 [Google Scholar]
  45. Goldstein JL, DeBose-Boyd RA, Brown MS. 45.  2006. Protein sensors for membrane sterols. Cell 124:135–46 [Google Scholar]
  46. Gong Y, Lee JN, Lee PC, Goldstein JL, Brown MS, Ye J. 46.  2006. Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Cell Metab. 3:115–24 [Google Scholar]
  47. Greenblatt EJ, Olzmann JA, Kopito RR. 47.  2012. Making the cut: intramembrane cleavage by a rhomboid protease promotes ERAD. Nat. Struct. Mol. Biol. 19:10979–81 [Google Scholar]
  48. Grove DE, Fan CY, Ren HY, Cyr DM. 48.  2011. The endoplasmic reticulum–associated Hsp40 DNAJB12 and Hsc70 cooperate to facilitate RMA1 E3-dependent degradation of nascent CFTRΔF508. Mol. Biol. Cell 22:3301–14 [Google Scholar]
  49. Guerriero CJ, Brodsky JL. 49.  2012. The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Physiol. Rev. 92:2537–76 [Google Scholar]
  50. Gusarova V, Caplan AJ, Brodsky JL, Fisher EA. 50.  2001. Apoprotein B degradation is promoted by the molecular chaperones hsp90 and hsp70. J. Biol. Chem. 276:2724891–900 [Google Scholar]
  51. Habeck G, Ebner FA, Shimada-Kreft H, Kreft SG. 51.  2015. The yeast ERAD-C ubiquitin ligase Doa10 recognizes an intramembrane degron. J. Cell Biol. 209:2261–73 [Google Scholar]
  52. Hagiwara M, Maegawa K, Suzuki M, Ushioda R, Araki K. 52.  et al. 2011. Structural basis of an ERAD pathway mediated by the ER-resident protein disulfide reductase ERdj5. Mol. Cell 41:4432–44 [Google Scholar]
  53. Hannah VC, Ou J, Luong A, Goldstein JL, Brown MS. 53.  2001. Unsaturated fatty acids down-regulate SREBP isoforms 1a and 1c by two mechanisms in HEK-293 cells. J. Biol. Chem. 276:64365–72 [Google Scholar]
  54. Hartman IZ, Liu P, Zehmer JK, Luby-Phelps K, Jo Y. 54.  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. 285:2519288–98 [Google Scholar]
  55. Hebert DN, Foellmer B, Helenius A. 55.  1995. Glucose trimming and reglucosylation determine glycoprotein association with calnexin in the endoplasmic reticulum. Cell 81:3425–33 [Google Scholar]
  56. Heinemann FS, Korza G, Ozols J. 56.  2003. A plasminogen-like protein selectively degrades stearoyl-CoA desaturase in liver microsomes. J. Biol. Chem. 278:4442966–75 [Google Scholar]
  57. Horton JD, Goldstein JL, Brown MS. 57.  2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J. Clin. Investig. 109:91125–31 [Google Scholar]
  58. Horton JD, Shah NA, Warrington JA, Anderson NN, Park SW. 58.  et al. 2003. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. PNAS 100:2112027–32 [Google Scholar]
  59. Hosokawa N, Kamiya Y, Kamiya D, Kato K, Nagata K. 59.  2009. Human OS-9, a lectin required for glycoprotein endoplasmic reticulum-associated degradation, recognizes mannose-trimmed N-glycans. J. Biol. Chem. 284:2517061–68 [Google Scholar]
  60. Hosokawa N, Wada I, Nagasawa K, Moriyama T, Okawa K, Nagata K. 60.  2008. Human XTP3-B forms an endoplasmic reticulum quality control scaffold with the HRD1-SEL1L ubiquitin ligase complex and BiP. J. Biol. Chem. 283:3020914–24 [Google Scholar]
  61. Howe V, Chua NK, Stevenson J, Brown AJ. 61.  2015. The regulatory domain of squalene monooxygenase contains a re-entrant loop and senses cholesterol via a conformational change. J. Biol. Chem. 290:4627533–44 [Google Scholar]
  62. Huber MD, Vesely PW, Datta K, Gerace L. 62.  2013. Erlins restrict SREBP activation in the ER and regulate cellular cholesterol homeostasis. J. Cell Biol. 203:3427–36 [Google Scholar]
  63. Hulce JJ, Cognetta AB, Niphakis MJ, Tully SE, Cravatt BF. 63.  2013. Proteome-wide mapping of cholesterol-interacting proteins in mammalian cells. Nat. Methods 10:3259–64 [Google Scholar]
  64. Ikeda Y, Demartino GN, Brown MS, Lee JN, Goldstein JL, Ye J. 64.  2009. Regulated endoplasmic reticulum-associated degradation of a polytopic protein: P97 recruits proteasomes to Insig-1 before extraction from membranes. J. Biol. Chem. 284:5034889–900 [Google Scholar]
  65. Inoue S, Bar-Nun S, Roitelman J, Simoni RD. 65.  1991. Inhibition of degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase in vivo by cysteine protease inhibitors. J. Biol. Chem. 266:2013311–17 [Google Scholar]
  66. Inoue T, Tsai B. 66.  2011. A large and intact viral particle penetrates the endoplasmic reticulum membrane to reach the cytosol. PLOS Pathog. 7:5e1002037 [Google Scholar]
  67. Irisawa M, Inoue J, Ozawa N, Mori K, Sato R. 67.  2009. The sterol-sensing endoplasmic reticulum (ER) membrane protein TRC8 hampers ER to Golgi transport of sterol regulatory element-binding protein-2 (SREBP-2)/SREBP cleavage-activated protein and reduces SREBP-2 cleavage. J. Biol. Chem. 284:4228995–9004 [Google Scholar]
  68. Jeon YJ, Khelifa S, Ratnikov B, Scott DA, Feng Y. 68.  et al. 2015. Regulation of glutamine carrier proteins by RNF5 determines breast cancer response to ER stress-inducing chemotherapies. Cancer Cell 27:3354–69 [Google Scholar]
  69. Jin L, Pahuja KB, Wickliffe KE, Gorur A, Baumgärtel C. 69.  et al. 2012. Ubiquitin-dependent regulation of COPII coat size and function. Nature 482:7386495–500 [Google Scholar]
  70. Jo Y, Hartman IZ, DeBose-Boyd RA. 70.  2013. 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 24:3169–83 [Google Scholar]
  71. Jo Y, Lee PC, Sguigna PV, DeBose-Boyd RA. 71.  2011. Sterol-induced degradation of HMG CoA reductase depends on interplay of two Insigs and two ubiquitin ligases, gp78 and Trc8. PNAS 108:5120503–8 [Google Scholar]
  72. Jo Y, Sguigna PV, DeBose-Boyd RA. 72.  2011. Membrane-associated ubiquitin ligase complex containing gp78 mediates sterol-accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J. Biol. Chem. 286:1715022–31 [Google Scholar]
  73. Johnston JA, Ward CL, Kopito RR. 73.  1998. Aggresomes: a cellular response to misfolded proteins. J. Cell Biol. 143:71883–98 [Google Scholar]
  74. Kato H, Sakaki K, Mihara K. 74.  2006. Ubiquitin-proteasome-dependent degradation of mammalian ER stearoyl-CoA desaturase. J. Cell Sci. 119:2342–53 [Google Scholar]
  75. Khmelinskii A, Blaszczak E, Pantazopoulou M, Fischer B, Omnus DJ. 75.  et al. 2014. Protein quality control at the inner nuclear membrane. Nature 516:7531410–13 [Google Scholar]
  76. Kikkert M, Doolman R, Dai M, Avner R, Hassink G. 76.  et al. 2004. Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum. J. Biol. Chem. 279:53525–34 [Google Scholar]
  77. Kim H, Zhang H, Meng D, Russell G, Lee JN, Ye J. 77.  2013. UAS domain of Ubxd8 and FAF1 polymerizes upon interaction with long-chain unsaturated fatty acids. J. Lipid Res. 54:82144–52 [Google Scholar]
  78. Klemm EJ, Spooner E, Ploegh HL. 78.  2011. Dual role of ancient ubiquitous protein 1 (AUP1) in lipid droplet accumulation and endoplasmic reticulum (ER) protein quality control. J. Biol. Chem. 286:4337602–14 [Google Scholar]
  79. Komander D, Rape M. 79.  2012. The ubiquitin code. Annu. Rev. Biochem. 81:203–29 [Google Scholar]
  80. Kristiana I, Luu W, Stevenson J, Cartland S, Jessup W. 80.  et al. 2012. Cholesterol through the looking glass: ability of its enantiomer also to elicit homeostatic responses. J. Biol. Chem. 287:4033897–904 [Google Scholar]
  81. Lange Y, Ory DS, Ye J, Lanier MH, Hsu FF, Steck TL. 81.  2008. Effectors of rapid homeostatic responses of endoplasmic reticulum cholesterol and 3-hydroxy-3-methylglutaryl-CoA reductase. J. Biol. Chem. 283:31445–55 [Google Scholar]
  82. Lass A, Zimmermann R, Oberer M, Zechner R. 82.  2011. Lipolysis—a highly regulated multi-enzyme complex mediates the catabolism of cellular fat stores. Prog. Lipid Res. 50:114–27 [Google Scholar]
  83. Lee JN, Gong Y, Zhang X, Ye J. 83.  2006. Proteasomal degradation of ubiquitinated Insig proteins is determined by serine residues flanking ubiquitinated lysines. PNAS 103:134958–63 [Google Scholar]
  84. Lee JN, Kim H, Yao H, Chen Y, Weng K, Ye J. 84.  2010. Identification of Ubxd8 protein as a sensor for unsaturated fatty acids and regulator of triglyceride synthesis. PNAS 107:5021424–29 [Google Scholar]
  85. Lee JN, Song B, DeBose-Boyd RA, Ye J. 85.  2006. Sterol-regulated degradation of Insig-1 mediated by the membrane-bound ubiquitin ligase gp78. J. Biol. Chem. 281:5139308–15 [Google Scholar]
  86. Lee JN, Ye J. 86.  2004. Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1. J. Biol. Chem. 279:4345257–65 [Google Scholar]
  87. Lee JN, Zhang X, Feramisco JD, Gong Y, Ye J. 87.  2008. Unsaturated fatty acids inhibit proteasomal degradation of Insig-1 at a postubiquitination step. J. Biol. Chem. 283:4833772–83 [Google Scholar]
  88. Lee JP, Brauweiler A, Rudolph M, Hooper JE, Drabkin HA, Gemmill RM. 88.  2010. The Trc8 ubiquitin ligase is sterol regulated and interacts with lipid and protein biosynthetic pathways. Mol. Cancer Res. 8:193–106 [Google Scholar]
  89. Lee PC, Nguyen AD, Debose-Boyd RA. 89.  2007. Mutations within the membrane domain of HMG-CoA reductase confer resistance to sterol-accelerated degradation. J. Lipid Res. 48:2318–27 [Google Scholar]
  90. Lee PC, Sever N, Debose-Boyd RA. 90.  2005. Isolation of sterol-resistant Chinese hamster ovary cells with genetic deficiencies in both Insig-1 and Insig-2. J. Biol. Chem. 280:2625242–49 [Google Scholar]
  91. Lee RJ, Liu CW, Harty C, McCracken AA, Latterich M. 91.  et al. 2004. Uncoupling retro-translocation and degradation in the ER-associated degradation of a soluble protein. EMBO J. 23:112206–15 [Google Scholar]
  92. Leichner GS, Avner R, Harats D, Roitelman J. 92.  2009. Dislocation of HMG-CoA reductase and Insig-1, two polytopic endoplasmic reticulum proteins, en route to proteasomal degradation. Mol. Biol. Cell 20:143330–41 [Google Scholar]
  93. Lev S. 93.  2012. Nonvesicular lipid transfer from the endoplasmic reticulum. Cold Spring Harb. Perspect. Biol. 4:10a013300 [Google Scholar]
  94. Liang J, Wu X, Jiang H, Zhou M, Yang H. 94.  et al. 1998. Translocation efficiency, susceptibility to proteasomal degradation, and lipid responsiveness of apolipoprotein B are determined by the presence of β sheet domains. J. Biol. Chem. 273:5235216–21 [Google Scholar]
  95. Liang JS, Kim T, Fang S, Yamaguchi J, Weissman AM. 95.  et al. 2003. 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. 278:2623984–88 [Google Scholar]
  96. Lilley BN, Ploegh HL. 96.  2004. A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429:6994834–40 [Google Scholar]
  97. Lipson C, Alalouf G, Bajorek M, Rabinovich E, Atir-Lande A. 97.  et al. 2008. A proteasomal ATPase contributes to dislocation of endoplasmic reticulum-associated degradation (ERAD) substrates. J. Biol. Chem. 283:117166–75 [Google Scholar]
  98. Listenberger LL, Han X, Lewis SE, Cases S, Farese RV. 98.  et al. 2003. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. PNAS 100:63077–82 [Google Scholar]
  99. Liu TF, Tang JJ, Li PS, Shen Y, Li JG. 99.  et al. 2012. Ablation of gp78 in liver improves hyperlipidemia and insulin resistance by inhibiting SREBP to decrease lipid biosynthesis. Cell Metab. 16:2213–25 [Google Scholar]
  100. Liu Y, Soetandyo N, Lee JG, Liu L, Xu Y. 100.  et al. 2014. USP13 antagonizes gp78 to maintain functionality of a chaperone in ER-associated degradation. eLife 3:e01369 [Google Scholar]
  101. Lu JP, Wang Y, Sliter DA, Pearce MM, Wojcikiewicz RJ. 101.  2011. RNF170 protein, an endoplasmic reticulum membrane ubiquitin ligase, mediates inositol 1,4,5-trisphosphate receptor ubiquitination and degradation. J. Biol. Chem. 286:2724426–33 [Google Scholar]
  102. Lukacs GL, Verkman AS. 102.  2012. CFTR: folding, misfolding and correcting the ΔF508 conformational defect. Trends Mol. Med. 18:281–91 [Google Scholar]
  103. Malhotra V, Erlmann P. 103.  2011. Protein export at the ER: loading big collagens into COPII carriers. EMBO J. 30:173475–80 [Google Scholar]
  104. Man WC, Miyazaki M, Chu K, Ntambi J. 104.  2006. Colocalization of SCD1 and DGAT2: implying preference for endogenous monounsaturated fatty acids in triglyceride synthesis. J. Lipid Res. 47:91928–39 [Google Scholar]
  105. Martínez-Botas J. 105.  2001. Dose-dependent effects of lovastatin on cell cycle progression: distinct requirement of cholesterol and non-sterol mevalonate derivatives. Biochim. Biophys. Acta 15323185–94 [Google Scholar]
  106. Matsumura Y, Sakai J, Skach WR. 106.  2013. Endoplasmic reticulum protein quality control is determined by cooperative interactions between Hsp/c70 and the CHIP E3 ligase. J. Biol. Chem. 288:4331069–79 [Google Scholar]
  107. Matyskiela ME, Martin A. 107.  2013. Design principles of a universal protein degradation machine. J. Mol. Biol. 425:2199–213 [Google Scholar]
  108. Maxfield FR, Tabas I. 108.  2005. Role of cholesterol and lipid organization in disease. Nature 438:7068612–21 [Google Scholar]
  109. McFie PJ, Jin Y, Banman SL, Beauchamp E, Berthiaume LG, Stone SJ. 109.  2014. Characterization of the interaction of diacylglycerol acyltransferase-2 with the endoplasmic reticulum and lipid droplets. Biochim. Biophys. Acta 1841:91318–28 [Google Scholar]
  110. Mehnert M, Sommer T, Jarosch E. 110.  2014. Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane. Nat. Cell Biol. 16:177–86 [Google Scholar]
  111. Meinecke M, Cizmowski C, Schliebs W, Krüger V, Beck S. 111.  et al. 2010. The peroxisomal importomer constitutes a large and highly dynamic pore. Nat. Cell Biol. 12:3273–77 [Google Scholar]
  112. Meyer H, Bug M, Bremer S. 112.  2012. Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nat. Cell Biol. 14:2117–23 [Google Scholar]
  113. Miao H, Jiang W, Ge L, Li B, Song B. 113.  2010. Tetra-glutamic acid residues adjacent to Lys248 in HMG-CoA reductase are critical for the ubiquitination mediated by gp78 and UBE2G2. Acta Biochim. Biophys. Sin. 42:5303–10 [Google Scholar]
  114. Mitchell DM, Zhou M, Pariyarath R, Wang H, Aitchison JD. 114.  et al. 1998. Apoprotein B100 has a prolonged interaction with the translocon during which its lipidation and translocation change from dependence on the microsomal triglyceride transfer protein to independence. PNAS 95:2514733–38 [Google Scholar]
  115. Moldavski O, Amen T, Levin-Zaidman S, Eisenstein M, Rogachev I. 115.  et al. 2015. Lipid droplets are essential for efficient clearance of cytosolic inclusion bodies. Dev. Cell 33:5603–10 [Google Scholar]
  116. Morito D, Hirao K, Oda Y, Hosokawa N, Tokunaga F. 116.  et al. 2008. Gp78 cooperates with RMA1 in endoplasmic reticulum-associated degradation of CFTRΔF508. Mol. Biol. Cell 19:41328–36 [Google Scholar]
  117. Morris LL, Hartman IZ, Jun DJ, Seemann J, DeBose-Boyd RA. 117.  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. 289:2719053–66 [Google Scholar]
  118. Motamed M, Zhang Y, Wang ML, Seemann J, Kwon HJ. 118.  et al. 2011. Identification of luminal Loop 1 of Scap protein as the sterol sensor that maintains cholesterol homeostasis. J. Biol. Chem. 286:2018002–12 [Google Scholar]
  119. Mueller B, Klemm EJ, Spooner E, Claessen JH, Ploegh HL. 119.  2008. SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins. PNAS 105:3412325–30 [Google Scholar]
  120. Mziaut H, Korza G, Ozols J. 120.  2000. The N terminus of microsomal Δ9 stearoyl-CoA desaturase contains the sequence determinant for its rapid degradation. PNAS 97:168883–88 [Google Scholar]
  121. Nakakuki M, Kawano H, Notsu T, Imada K, Mizuguchi K, Shimano H. 121.  2014. A novel processing system of sterol regulatory element-binding protein-1c regulated by polyunsaturated fatty acid. J. Biochem. 155:5301–13 [Google Scholar]
  122. Nakanishi SM, Goldstein L, Brown S. 122.  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. 263:188929–37 [Google Scholar]
  123. Nakatsukasa K, Huyer G, Michaelis S, Brodsky JL. 123.  2008. Dissecting the ER-associated degradation of a misfolded polytopic membrane protein. Cell 132:1101–12 [Google Scholar]
  124. Nguyen AD, Lee SH, DeBose-Boyd RA. 124.  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. 284:3926778–88 [Google Scholar]
  125. Nguyen AD, McDonald JG, Bruick RK, DeBose-Boyd RA. 125.  2007. 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. 282:3727436–46 [Google Scholar]
  126. Ninagawa S, Okada T, Sumitomo Y, Horimoto S, Sugimoto T. 126.  et al. 2015. Forcible destruction of severely misfolded mammalian glycoproteins by the non-glycoprotein ERAD pathway. J. Cell Biol. 211:4775–84 [Google Scholar]
  127. Ninagawa S, Okada T, Sumitomo Y, Kamiya Y, Kato K. 127.  et al. 2014. EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step. J. Cell Biol. 206:3347–56 [Google Scholar]
  128. Ohsaki Y, Cheng J, Fujita A, Tokumoto T, Fujimoto T. 128.  2006. Cytoplasmic lipid droplets are sites of convergence of proteasomal and autophagic degradation of apolipoprotein B. Mol. Biol. Cell 17:62674–83 [Google Scholar]
  129. Ohsaki Y, Cheng J, Suzuki M, Fujita A, Fujimoto T. 129.  2008. Lipid droplets are arrested in the ER membrane by tight binding of lipidated apolipoprotein B-100. J. Cell Sci. 121:2415–22 [Google Scholar]
  130. Okuda-Shimizu Y, Hendershot LM. 130.  2007. Characterization of an ERAD pathway for nonglycosylated BiP substrates, which require Herp. Mol. Cell 28:4544–54 [Google Scholar]
  131. Olzmann JA, Kopito RR. 131.  2011. Lipid droplet formation is dispensable for endoplasmic reticulum-associated degradation. J. Biol. Chem. 286:3227872–74 [Google Scholar]
  132. Olzmann JA, Kopito RR, Christianson JC. 132.  2013. The mammalian endoplasmic reticulum-associated degradation system. Cold Spring Harb. Perspect. Biol. 5:9a013185 [Google Scholar]
  133. Olzmann JA, Richter CM, Kopito RR. 133.  2013. Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover. PNAS 110:41345–50 [Google Scholar]
  134. Ou J, Tu H, Shan B, Luk A, DeBose-Boyd RA. 134.  et al. 2001. Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c) gene by antagonizing ligand-dependent activation of the LXR. PNAS 98:116027–32 [Google Scholar]
  135. Pearce MM, Wormer DB, Wilkens S, Wojcikiewicz RJ. 135.  2009. An endoplasmic reticulum (ER) membrane complex composed of SPFH1 and SPFH2 mediates the ER-associated degradation of inositol 1,4,5-trisphosphate receptors. J. Biol. Chem. 284:1610433–45 [Google Scholar]
  136. Petris G, Casini A, Sasset L, Cesaratto F, Bestagno M. 136.  et al. 2014. CD4 and BST-2/tetherin proteins retro-translocate from endoplasmic reticulum to cytosol as partially folded and multimeric molecules. J. Biol. Chem. 289:11–12 [Google Scholar]
  137. Plemper K, Bohmler S, Bordallo J, Sommer T. 137.  1997. Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation. Nature 388:6645891–95 [Google Scholar]
  138. Ploegh HL. 138.  2007. A lipid-based model for the creation of an escape hatch from the endoplasmic reticulum. Nature 448:7152435–38 [Google Scholar]
  139. Pol A, Gross SP, Parton RG. 139.  2014. Biogenesis of the multifunctional lipid droplet: lipids, proteins, and sites. J. Cell Biol. 204:5635–46 [Google Scholar]
  140. Prinz WA. 140.  2014. Bridging the gap: membrane contact sites in signaling, metabolism, and organelle dynamics. J. Cell Biol. 205:6759–69 [Google Scholar]
  141. Radhakrishnan A, Goldstein JL, McDonald JG, Brown MS. 141.  2008. Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance. Cell Metab. 8:6512–21 [Google Scholar]
  142. Radhakrishnan A, Ikeda Y, Kwon HJ, Brown MS, Goldstein JL. 142.  2007. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Oxysterols block transport by binding to Insig. PNAS 104:166511–18 [Google Scholar]
  143. Rapoport TA. 143.  2007. Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes. Nature 450:7170663–69 [Google Scholar]
  144. Ruggiano A, Foresti O, Carvalho P. 144.  2014. ER-associated degradation: protein quality control and beyond. J. Cell Biol. 204:6869–79 [Google Scholar]
  145. Rutledge AC, Qiu W, Zhang R, Kohen-Avramoglu R, Nemat-Gorgani N, Adeli K. 145.  2009. Mechanisms targeting apolipoprotein B100 to proteasomal degradation: evidence that degradation is initiated by BiP binding at the N terminus and the formation of a p97 complex at the C terminus. Arterioscler. Thromb. Vasc. Biol. 29:4579–85 [Google Scholar]
  146. Sato BK, Schulz D, Do PH, Hampton RY. 146.  2009. Misfolded membrane proteins are specifically recognized by the transmembrane domain of the Hrd1p ubiquitin ligase. Mol. Cell 34:2212–22 [Google Scholar]
  147. Sato R, Goldstein JL, Brown MS. 147.  1993. Replacement of serine-871 of hamster 3-hydroxy-3-methylglutaryl-CoA reductase prevents phosphorylation by AMP-activated kinase and blocks inhibition of sterol synthesis induced by ATP depletion. PNAS 90:209261–65 [Google Scholar]
  148. Sato T, Sako Y, Sho M, Momohara M, Suico MA. 148.  et al. 2012. STT3B-dependent posttranslational N-glycosylation as a surveillance system for secretory protein. Mol. Cell 47:199–110 [Google Scholar]
  149. Sato T, Susuki S, Suico MA, Miyata M, Ando Y. 149.  et al. 2007. Endoplasmic reticulum quality control regulates the fate of transthyretin variants in the cell. EMBO J. 26:102501–12 [Google Scholar]
  150. Satoh T, Chen Y, Hu D, Hanashima S, Yamamoto K, Yamaguchi Y. 150.  2010. Structural basis for oligosaccharide recognition of misfolded glycoproteins by OS-9 in ER-associated degradation. Mol. Cell 40:6905–16 [Google Scholar]
  151. Schliebs W, Girzalsky W, Erdmann R. 151.  2010. Peroxisomal protein import and ERAD: variations on a common theme. Nat. Rev. Mol. Cell Biol. 11:12885–90 [Google Scholar]
  152. Schumacher MM, Elsabrouty R, Seemann J, Jo Y, DeBose-Boyd RA. 152.  2015. The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase. eLife 4e05560 [Google Scholar]
  153. Sekijima Y, Wiseman RL, Matteson J, Hammarström P, Miller SR. 153.  et al. 2005. The biological and chemical basis for tissue-selective amyloid disease. Cell 121:173–85 [Google Scholar]
  154. Sever N, Song BL, Yabe D, Goldstein JL, Brown MS, DeBose-Boyd RA. 154.  2003. Insig-dependent ubiquitination and degradation of mammalian 3-hydroxy-3-methylglutaryl-CoA reductase stimulated by sterols and geranylgeraniol. J. Biol. Chem. 278:5252479–90 [Google Scholar]
  155. Sever N, Yang T, Brown MS, Goldstein JL, DeBose-Boyd RA. 155.  2003. Accelerated degradation of HMG CoA reductase mediated by binding of Insig-1 to its sterol-sensing domain. Mol. Cell 11:125–33 [Google Scholar]
  156. Shao S, Hegde RS. 156.  2011. Membrane protein insertion at the endoplasmic reticulum. Annu. Rev. Cell Dev. Biol. 27:25–56 [Google Scholar]
  157. Shearer AG, Hampton RY. 157.  2004. Structural control of endoplasmic reticulum-associated degradation: effect of chemical chaperones on 3-hydroxy-3-methylglutaryl-CoA reductase. J. Biol. Chem. 279:1188–96 [Google Scholar]
  158. Shearer AG, Hampton RY. 158.  2005. Lipid-mediated, reversible misfolding of a sterol-sensing domain protein. EMBO J. 24:1149–59 [Google Scholar]
  159. Shelness GS, Ledford AS. 159.  2005. Evolution and mechanism of apolipoprotein B-containing lipoprotein assembly. Curr. Opin. Lipidol. 16:3325–32 [Google Scholar]
  160. Shrimal S, Cherepanova NA, Gilmore R. 160.  2015. Cotranslational and posttranslocational N-glycosylation of proteins in the endoplasmic reticulum. Semin. Cell Dev. Biol. 41:71–78 [Google Scholar]
  161. Simons K, Ikonen E. 161.  2000. How cells handle cholesterol. Science 290:54971721–26 [Google Scholar]
  162. Simons K, Toomre D. 162.  2000. Lipid rafts and signal transduction. Nat. Rev. Mol. Cell Biol. 1:131–39 [Google Scholar]
  163. Simons K, Vaz WL. 163.  2004. Model systems, lipid rafts, and cell membranes. Annu. Rev. Biophys. Biomol. Struct. 33:269–95 [Google Scholar]
  164. Skalnik DG, Narita H, Kent C, Simoni RD. 164.  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. 263:146836–41 [Google Scholar]
  165. Song BL, DeBose-Boyd RA. 165.  2004. 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. 279:2728798–806 [Google Scholar]
  166. Song BL, Sever N, DeBose-Boyd RA. 166.  2005. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol. Cell 19:6829–40 [Google Scholar]
  167. Stagg HR, Thomas M, van den Boomen D, Wiertz EJ, Drabkin HA. 167.  et al. 2009. The Trc8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER. J. Cell Biol. 186:5685–92 [Google Scholar]
  168. Steck TL, Lange Y. 168.  2010. Cell cholesterol homeostasis: mediation by active cholesterol. Trends Cell Biol. 20:11680–87 [Google Scholar]
  169. Stein A, Ruggiano A, Carvalho P, Rapoport TA. 169.  2014. Key steps in ERAD of luminal ER proteins reconstituted with purified components. Cell 158:61375–88 [Google Scholar]
  170. Stevenson J, Luu W, Kristiana I, Brown AJ. 170.  2014. Squalene mono-oxygenase, a key enzyme in cholesterol synthesis, is stabilized by unsaturated fatty acids. Biochem J. 461:3435–42 [Google Scholar]
  171. Stone SJ, Levin MC, Farese RV. 171.  2006. Membrane topology and identification of key functional amino acid residues of murine acyl-CoA:diacylglycerol acyltransferase-2. J. Biol. Chem. 281:5240273–82 [Google Scholar]
  172. Sun LP, Seemann J, Goldstein JL, Brown MS. 172.  2007. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in SCAP inaccessible to COPII proteins. PNAS 104:166519–26 [Google Scholar]
  173. Sun S, Shi G, Sha H, Ji Y, Han X. 173.  et al. 2015. IRE1α is an endogenous substrate of endoplasmic-reticulum-associated degradation. Nat. Cell Biol. 17:1546–55 [Google Scholar]
  174. Suzuki M, Otsuka T, Ohsaki Y, Cheng J, Taniguchi T. 174.  et al. 2012. Derlin-1 and UBXD8 are engaged in dislocation and degradation of lipidated ApoB-100 at lipid droplets. Mol. Biol. Cell 23:5800–10 [Google Scholar]
  175. Tannous A, Patel N, Tamura T, Hebert DN. 175.  2015. Reglucosylation by UDP-glucose:glycoprotein glucosyltransferase 1 delays glycoprotein secretion but not degradation. Mol. Biol. Cell 26:3390–405 [Google Scholar]
  176. Tannous A, Pisoni GB, Hebert DN, Molinari M. 176.  2015. N-linked sugar-regulated protein folding and quality control in the ER. Semin. Cell Dev. Biol. 41:79–89 [Google Scholar]
  177. Thibault G, Ng DT. 177.  2012. The endoplasmic reticulum-associated degradation pathways of budding yeast. Cold Spring Harb. Perspect. Biol. 4:12a013193 [Google Scholar]
  178. Tirosh B, Furman MH, Tortorella D, Ploegh HL. 178.  2003. Protein unfolding is not a prerequisite for endoplasmic reticulum-to-cytosol dislocation. J. Biol. Chem. 278:96664–72 [Google Scholar]
  179. Toyama T, Kudo N, Mitsumoto A, Hibino Y, Tsuda T, Kawashima Y. 179.  2007. Stearoyl-CoA desaturase activity is elevated by the suppression of its degradation by clofibric acid in the liver of rats. J. Pharmacol. Sci. 103:4383–90 [Google Scholar]
  180. Tsai YC, Leichner GS, Pearce MM, Wilson GL, Wojcikiewicz RJ. 180.  et al. 2012. Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system. Mol. Biol. Cell 23:234484–94 [Google Scholar]
  181. Tyler RE, Pearce MM, Shaler TA, Olzmann JA, Greenblatt EJ, Kopito RR. 181.  2012. Unassembled CD147 is an endogenous endoplasmic reticulum-associated degradation substrate. Mol. Biol. Cell 23:244668–78 [Google Scholar]
  182. Ushioda R, Hoseki J, Araki K, Jansen G, Thomas DY, Nagata K. 182.  2008. ERdj5 is required as a disulfide reductase for degradation of misfolded proteins in the ER. Science 321:5888569–72 [Google Scholar]
  183. Ushioda R, Hoseki J, Nagata K. 183.  2013. Glycosylation-independent ERAD pathway serves as a backup system under ER stress. Mol. Biol. Cell 24:203155–63 [Google Scholar]
  184. Van de Weijer ML, Bassik MC, Luteijn RD, Voorburg CM, Lohuis MA. 184.  et al. 2014. A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation. Nat. Commun. 5:3832 [Google Scholar]
  185. Van den Berg B, Clemons WM, Collinson I, Modis Y, Hartmann E. 185.  et al. 2004. X-ray structure of a protein-conducting channel. Nature 427:696936–44 [Google Scholar]
  186. Van den Boomen DJ, Lehner PJ. 186.  2015. Identifying the ERAD ubiquitin E3 ligases for viral and cellular targeting of MHC class I. Mol. Immunol. 68:2106–11 [Google Scholar]
  187. Van den Boomen DJ, Timms RT, Grice GL, Stagg HR, Skødt K. 187.  et al. 2014. TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I. PNAS 111:3111425–30 [Google Scholar]
  188. Voorhees RM, Fernández IS, Scheres SH, Hegde RS. 188.  2014. Structure of the mammalian ribosome–Sec61 complex to 3.4 Å resolution. Cell 157:71632–43 [Google Scholar]
  189. Walther TC, Farese RV. 189.  2012. Lipid droplets and cellular lipid metabolism. Annu. Rev. Biochem. 81:687–714 [Google Scholar]
  190. Wang CW, Lee SC. 190.  2012. The ubiquitin-like (UBX)-domain-containing protein Ubx2/Ubxd8 regulates lipid droplet homeostasis. J. Cell Sci. 125:2930–39 [Google Scholar]
  191. Wang Q, Li L, Ye Y. 191.  2008. Inhibition of p97-dependent protein degradation by eeyarestatin I. J. Biol. Chem. 283:127445–54 [Google Scholar]
  192. Wang Q, Liu Y, Soetandyo N, Baek K, Hegde R, Ye Y. 192.  2011. A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation. Mol. Cell 42:6758–70 [Google Scholar]
  193. Ward CL, Omura S, Kopito RR. 193.  1995. Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 83:1121–27 [Google Scholar]
  194. Wilfling F, Wang H, Haas JT, Krahmer N, Gould TJ. 194.  et al. 2013. Triacylglycerol synthesis enzymes mediate lipid droplet growth by relocalizing from the ER to lipid droplets. Dev. Cell 24:4384–99 [Google Scholar]
  195. Wojcikiewicz RJ, Pearce MM, Sliter DA, Wang Y. 195.  2009. When worlds collide: IP3 receptors and the ERAD pathway. Cell Calcium 46:3147–53 [Google Scholar]
  196. Wong J, Quinn CM, Gelissen IC, Brown AJ. 196.  2008. Endogenous 24(S),25-epoxycholesterol fine-tunes acute control of cellular cholesterol homeostasis. J. Biol. Chem. 283:2700–7 [Google Scholar]
  197. Xu C, Ng DT. 197.  2015. Glycosylation-directed quality control of protein folding. Nat. Rev. Mol. Cell Biol. 16:12742–52 [Google Scholar]
  198. Xu Y, Cai M, Yang Y, Huang L, Ye Y. 198.  2012. SGTA recognizes a noncanonical ubiquitin-like domain in the Bag6–Ubl4A–Trc35 complex to promote endoplasmic reticulum-associated degradation. Cell Rep. 2:61633–44 [Google Scholar]
  199. Xu Y, Liu Y, Lee JG, Ye Y. 199.  2013. A ubiquitin-like domain recruits an oligomeric chaperone to a retrotranslocation complex in endoplasmic reticulum-associated degradation. J. Biol. Chem. 288:2518068–76 [Google Scholar]
  200. Yabe D, Brown MS, Goldstein JL. 200.  2002. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. PNAS 99:2012753–58 [Google Scholar]
  201. Yabe D, Xia ZP, Adams CM, Rawson RB. 201.  2002. Three mutations in sterol-sensing domain of SCAP block interaction with Insig and render SREBP cleavage insensitive to sterols. PNAS 99:2616672–77 [Google Scholar]
  202. Ye Y, Shibata Y, Yun C, Ron D, Rapoport TA. 202.  2004. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429:6994841–47 [Google Scholar]
  203. Yen CL, Stone SJ, Koliwad S, Harris C, Farese RV. 203.  2008. DGAT enzymes and triacylglycerol biosynthesis. J. Lipid Res. 49:112283–301 [Google Scholar]
  204. Yu H, Kaung G, Kobayashi S, Kopito RR. 204.  1997. Cytosolic degradation of T-cell receptor α chains by the proteasome. J. Biol. Chem. 272:3320800–4 [Google Scholar]
  205. Yu H, Kopito RR. 205.  1999. The role of multiubiquitination in dislocation and degradation of the α subunit of the T cell antigen receptor. J. Biol. Chem. 274:5236852–58 [Google Scholar]
  206. Zanetti G, Pahuja KB, Studer S, Shim S, Schekman R. 206.  2012. COPII and the regulation of protein sorting in mammals. Nat. Cell Biol. 14:120–28 [Google Scholar]
  207. Zehmer JK, Bartz R, Bisel B, Liu P, Seemann J, Anderson RG. 207.  2009. Targeting sequences of UBXD8 and AAM-B reveal that the ER has a direct role in the emergence and regression of lipid droplets. J. Cell Sci. 122:3694–702 [Google Scholar]
  208. Zelcer N, Sharpe LJ, Loregger A, Kristiana I, Cook EC. 208.  et al. 2014. The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase and affects 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and the cholesterol synthesis pathway. Mol. Cell Biol. 34:71262–70 [Google Scholar]
  209. Zettl M, Adrain C, Strisovsky K, Lastun V, Freeman M. 209.  2011. Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling. Cell 145:179–91 [Google Scholar]
  210. Zhang T, Xu Y, Liu Y, Ye Y. 210.  2015. Gp78 functions downstream of Hrd1 to promote degradation of misfolded proteins of the endoplasmic reticulum. Mol. Biol. Cell 26:244438–50 [Google Scholar]
  211. Zhang ZR, Bonifacino JS, Hegde RS. 211.  2013. Deubiquitinases sharpen substrate discrimination during membrane protein degradation from the ER. Cell 154:3609–22 [Google Scholar]
  212. Zhou M, Wu X, Huang LS, Ginsberg HN. 212.  1995. Apoprotein B100, an inefficiently translocated secretory protein, is bound to the cytosolic chaperone, heat shock protein 70. J. Biol. Chem. 270:4225220–24 [Google Scholar]

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