Ubiquitylation in the ERAD Pathway

Part of the Subcellular Biochemistry book series (SCBI, volume 54)


Ubiquitylation is a protein modification mechanism, which is found in a multitude of cellular processes like DNA repair and replication, cell signaling, intracellular trafficking and also, very prominently, in selective protein degradation. One specific protein degradation event in the cell concerns the elimination of misfolded proteins to prevent disastrous malfunctioning of cellular pathways. The most complex of these ubiquitylation dependent elimination pathways of misfolded proteins is associated with the endoplasmic reticulum (ER). Proteins, which enter the endoplasmic reticulum for secretion, are folded in this organelle and transported to their site of action. A rigid protein quality control check retains proteins in the endoplasmic reticulum, which fail to fold properly and sends them back to the cytosol for elimination by the proteasome. This requires crossing of the misfolded protein of the endoplasmic reticulum membrane and polyubiquitylation in the cytosol by the ubiquitin-activating, ubiquitin-conjugating and ubiquitin-ligating enzyme machinery.

Ubiquitylation is required for different steps of the ER-associated degradation process (ERAD). It facilitates efficient extraction of the ubiquitylated misfolded proteins from and out of the ER membrane by the Cdc48-Ufd1-Npl4 complex and thereby triggers their retro translocation to the cytosol. In addition, the modification with ubiquitin chains guarantees guidance, recognition and binding of the misfolded proteins to the proteasome in the cytosol for efficient degradation.


Endoplasmic Reticulum Protein Degradation UBIQUITIN Ligase Misfolded Protein Intracellular Trafficking 


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  1. 1.
    Sommer T, Wolf DH. Endoplasmic reticulum degradation: reverse protein flow of no return. FASEB J 1997; 11(14):1227–1233.PubMedGoogle Scholar
  2. 2.
    Plemper RK, Wolf DH. Retrograde protein translocation: ERADication of secretory proteins in health and disease. Trends Biochem Sci 1999; 24(7):266–270.PubMedGoogle Scholar
  3. 3.
    Brodsky JL, McCracken AA. ER protein quality control and proteasome-mediated protein degradation. Semin Cell Dev Biol 1999; 10(5):507–513.PubMedGoogle Scholar
  4. 4.
    Kostova Z, Wolf DH. For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection. EMBO J 2003; 22(10):2309–2317.PubMedGoogle Scholar
  5. 5.
    Hirsch C, Jarosch E, Sommer T et al. Endoplasmic reticulum-associated protein degradation—one model fits all? Biochim Biophys Acta 2004; 1695(1–3):215–223.PubMedGoogle Scholar
  6. 6.
    Meusser B, Hirsch C, Jarosch E et al. ERAD: the long road to destruction. Nat Cell Biol 2005; 7(8):766–772.PubMedGoogle Scholar
  7. 7.
    Vembar SS, Brodsky JL. One step at a time: endoplasmic reticulum-associated degradation. Nat Rev Mol Cell Biol 2008; 9(12):944–957.PubMedGoogle Scholar
  8. 8.
    Ellgaard L, Molinari M, Helenius A. Setting the standards: quality control in the secretory pathway. Science 1999; 286(5446):1882–1888.PubMedGoogle Scholar
  9. 9.
    Helenius A, Aebi M. Roles of N-linked glycans in the endoplasmic reticulum. Annu Rev Biochem 2004; 73:1019–1049.PubMedGoogle Scholar
  10. 10.
    Jakob CA, Burda P, Roth J et al. Degradation of misfolded endoplasmic reticulum glycoproteins in Saccharomyces cerevisiae is determined by a specific oligosaccharide structure. J Cell Biol 1998; 142(5):1223–1233.Google Scholar
  11. 11.
    Knop M, Hauser N, Wolf DH. N-Glycosylation affects endoplasmic reticulum degradation of a mutated derivative of carboxypeptidase yscY in yeast. Yeast 1996; 12(12):1229–1238.PubMedGoogle Scholar
  12. 12.
    Clerc S, Hirsch C, Oggier DM et al. Htm1 protein generates the N-glycan signal for glycoprotein degradation in the endoplasmic reticulum. J Cell Biol 2009; 184(1):159–172.PubMedGoogle Scholar
  13. 13.
    Quan EM, Kamiya Y, Kamiya D et al. Defining the glycan destruction signal for endoplasmic reticulum-associated degradation. Mol Cell 2008; 32(6):870–877.PubMedGoogle Scholar
  14. 14.
    Aebi M, Bernasconi R, Clerc S et al. N-glycan structures: recognition and processing in the ER. Trends Biochem Sci 2010; 35(2):74–82.PubMedGoogle Scholar
  15. 15.
    Gillece P, Luz JM, Lennarz WJ et al. Export of a cysteine-free misfolded secretory protein from the endoplasmic reticulum for degradation requires interaction with protein disulfide isomerase. J Cell Biol 1999; 147(7):1443–1456.PubMedGoogle Scholar
  16. 16.
    Sakoh-Nakatogawa M, Nishikawa S, Endo T. Roles of protein-disulfide isomerase-mediated disulfide bond formation of yeast Mnl1p in endoplasmic reticulum-associated degradation. J Biol Chem 2009; 284(18):11815–11825.PubMedGoogle Scholar
  17. 17.
    Ushioda R, Hoseki J, Araki K et al. ERdj5 is required as a disulfide reductase for degradation of misfolded proteins in the ER. Science 2008; 321(5888):569–572.Google Scholar
  18. 18.
    Denic V, Quan EM, Weissman JS. A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell 2006; 126(2):349–359.PubMedGoogle Scholar
  19. 19.
    Buschhorn BA, Kostova Z, Medicherla B et al. A genome-wide screen identifies Yos9p as essential for ER-associated degradation of glycoproteins. FEBS Lett 2004; 577(3):422–426.PubMedGoogle Scholar
  20. 20.
    Gauss R, Jarosch E, Sommer T et al. A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery. Nat Cell Biol 2006; 8(8):849–854.PubMedGoogle Scholar
  21. 21.
    Hosokawa N, Kamiya Y, Kamiya D et al. Human OS-9, a lectin required for glycoprotein endoplasmic reticulum-associated degradation, recognizes mannose-trimmed N-glycans. J Biol Chem 2009; 284(25):17061–17068.PubMedGoogle Scholar
  22. 22.
    Bernasconi R, Pertel T, Luban J et al. A dual task for the Xbp1-responsive OS-9 variants in the mammalian endoplasmic reticulum: inhibiting secretion of misfolded protein conformers and enhancing their disposal. J Biol Chem 2008; 283(24):16446–16454.PubMedGoogle Scholar
  23. 23.
    Christianson JC, Shaler TA, Tyler RE et al. OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD. Nat Cell Biol 2008; 10(3):272–282.PubMedGoogle Scholar
  24. 24.
    Mueller B, Klemm EJ, Spooner E et al. SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins. Proc Natl Acad Sci USA 2008; 105(34):12325–12330.PubMedGoogle Scholar
  25. 25.
    Mueller B, Lilley BN, Ploegh HL. SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER. J Cell Biol 2006; 175(2):261–270.PubMedGoogle Scholar
  26. 26.
    Kostova Z, Wolf DH. Importance of carbohydrate positioning in the recognition of mutated CPY for ER-associated degradation. J Cell Sci 2005; 118(Pt 7):1485–1492.PubMedGoogle Scholar
  27. 27.
    Spear ED, Ng DT. Single, context-specific glycans can target misfolded glycoproteins for ER-associated degradation. J Cell Biol 2005; 169(1):73–82.PubMedGoogle Scholar
  28. 28.
    Xie W, Kanehara K, Sayeed A et al. Intrinsic conformational determinants signal protein misfolding to the Hrd1/ Htm1 endoplasmic reticulum-associated degradation system. Mol Biol Cell 2009; 20(14):3317–3329.PubMedGoogle Scholar
  29. 29.
    Hiller MM, Finger A, Schweiger M et al. ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science 1996; 273(5282):1725–1728.PubMedGoogle Scholar
  30. 30.
    Finger A, Knop M, Wolf DH. Analysis of two mutated vacuolar proteins reveals a degradation pathway in the endoplasmic reticulum or a related compartment of yeast. Eur J Biochem 1993; 218(2):565–574.PubMedGoogle Scholar
  31. 31.
    Plemper RK, Deak PM, Otto RT et al. Re-entering the translocon from the lumenal side of the endoplasmic reticulum. Studies on mutated carboxypeptidase yscY species. FEBS Lett 1999; 443(3):241–245.PubMedGoogle Scholar
  32. 32.
    Friedlander R, Jarosch E, Urban J et al. A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nat Cell Biol 2000; 2(7):379–384.PubMedGoogle Scholar
  33. 33.
    Biederer T, Volkwein C, Sommer T. Role of Cue1p in ubiquitination and degradation at the ER surface. Science 1997; 278(5344):1806–1809.PubMedGoogle Scholar
  34. 34.
    Bordallo J, Plemper RK, Finger A et al. Der3p/Hrd1p is required for endoplasmic reticulum-associated degradation of misfolded lumenal and integral membrane proteins. Mol Biol Cell 1998; 9(1):209–222.PubMedGoogle Scholar
  35. 35.
    Deak PM, Wolf DH. Membrane topology and function of Der3/Hrd1p as a ubiquitin-protein ligase (E3) involved in endoplasmic reticulum degradation. J Biol Chem 2001; 276(14):10663–10669.PubMedGoogle Scholar
  36. 36.
    Bays NW, Gardner RG, Seelig LP et al. Hrd1p/Der3p is a membrane-anchored ubiquitin ligase required for ER-associated degradation. Nat Cell Biol 2001; 3(1):24–29.PubMedGoogle Scholar
  37. 37.
    Bordallo J, Wolf DH. A RING-H2 finger motif is essential for the function of Der3/Hrd1 in endoplasmic reticulum associated protein degradation in the yeast Saccharomyces cerevisiae. FEBS Lett 1999; 448(2–3):244–248.PubMedGoogle Scholar
  38. 38.
    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(12):2029–2044.PubMedGoogle Scholar
  39. 39.
    Plemper RK, Egner R, Kuchler K et al. Endoplasmic reticulum degradation of a mutated ATP-binding cassette transporter Pdr5 proceeds in a concerted action of Sec61 and the proteasome. J Biol Chem 1998; 273(49):32848–32856.PubMedGoogle Scholar
  40. 40.
    Carvalho P, Goder V, Rapoport TA. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 2006; 126(2):361–373.PubMedGoogle Scholar
  41. 41.
    Plemper RK, Bordallo J, Deak PM et al. Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro-translocation complex mediating protein transport for ER degradation. J Cell Sci 1999; 112(Pt 22):4123–4134.PubMedGoogle Scholar
  42. 42.
    Gardner RG, Swarbrick GM, Bays NW et al. Endoplasmic reticulum degradation requires lumen to cytosol signaling. Transmembrane control of Hrd1p by Hrd3p. J Cell Biol 2000; 151(1):69–82.PubMedGoogle Scholar
  43. 43.
    Hitt R, Wolf DH. Der1p, a protein required for degradation of malfolded soluble proteins of the endoplasmic reticulum: topology and Der1-like proteins. FEMS Yeast Res 2004; 4(7):721–729.PubMedGoogle Scholar
  44. 44.
    Knop M, Finger A, Braun T et al. Der1, a novel protein specifically required for endoplasmic reticulum degradation in yeast. EMBO J 1996; 15(4):753–763.PubMedGoogle Scholar
  45. 45.
    Horn SC, Hanna J, Hirsch C et al. Usa1 Functions as a Scaffold of the HRD-Ubiquitin Ligase. Mol Cell 2009; 36(5):782–793.PubMedGoogle Scholar
  46. 46.
    Kim I, Li Y, Muniz P et al. Usa1 protein facilitates substrate ubiquitylation through two separate domains. PLoS One 2009; 4(10):e7604.PubMedGoogle Scholar
  47. 47.
    Younger JM, Chen L, Ren HY et al. Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator. Cell 2006; 126(3):571–582.PubMedGoogle Scholar
  48. 48.
    Ye Y, Shibata Y, Yun C et al. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 2004; 429(6994):841–847.PubMedGoogle Scholar
  49. 49.
    Lilley BN, Ploegh HL. A membrane protein required for dislocation of misfolded proteins from the ER. Nature 2004; 429(6994):834–840.PubMedGoogle Scholar
  50. 50.
    Oda Y, Okada T, Yoshida H et al. Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J Cell Biol 2006; 172(3):383–393.PubMedGoogle Scholar
  51. 51.
    Schäfer A, Wolf DH. Sec61p is part of the endoplasmic reticulum-associated degradation machinery. EMBO J 2009; 28(19):2874–2884.PubMedGoogle Scholar
  52. 52.
    Plemper RK, Bohmler S, Bordallo J et al. Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation. Nature 1997; 388(6645):891–895.PubMedGoogle Scholar
  53. 53.
    Willer M, Forte GM, Stirling CJ. Sec61p is required for ERAD-L: genetic dissection of the translocation and ERAD-L functions of Sec61P using novel derivatives of CPY. J Biol Chem 2008; 283(49):33883–33888.PubMedGoogle Scholar
  54. 54.
    Shearer AG, Hampton RY. Lipid-mediated, reversible misfolding of a sterol-sensing domain protein. EMBO J 2005; 24(1):149–159.PubMedGoogle Scholar
  55. 55.
    Sato BK, Schulz D, Do PH et al. Misfolded membrane proteins are specifically recognized by the transmembrane domain of the Hrd1p ubiquitin ligase. Mol Cell 2009; 34(2):212–222.PubMedGoogle Scholar
  56. 56.
    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(6864):652–656.PubMedGoogle Scholar
  57. 57.
    Jarosch E, Taxis C, Volkwein C et al. Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat Cell Biol 2002; 4(2):134–139.PubMedGoogle Scholar
  58. 58.
    Bays NW, Wilhovsky SK, Goradia A et al. HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol Biol Cell 2001; 12(12):4114–4128.PubMedGoogle Scholar
  59. 59.
    Rabinovich E, Kerem A, Frohlich KU et al. AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol Cell Biol 2002; 22(2):626–634.PubMedGoogle Scholar
  60. 60.
    Braun S, Matuschewski K, Rape M et al. Role of the ubiquitin-selective CDC48(UFD1/NPL4) chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J 2002; 21(4):615–621.PubMedGoogle Scholar
  61. 61.
    Neuber O, Jarosch E, Volkwein C et al. Ubx2 links the Cdc48 complex to ER-associated protein degradation. Nat Cell Biol 2005; 7(10):993–998.PubMedGoogle Scholar
  62. 62.
    Schuberth C, Richly H, Rumpf S et al. Shp1 and Ubx2 are adaptors of Cdc48 involved in ubiquitin-dependent protein degradation. EMBO Rep 2004; 5(8):818–824.PubMedGoogle Scholar
  63. 63.
    Alberts SM, Sonntag C, Schafer A et al. Ubx4 modulates cdc48 activity and influences degradation of misfolded proteins of the endoplasmic reticulum. J Biol Chem 2009; 284(24):16082–16089.PubMedGoogle Scholar
  64. 64.
    Medicherla B, Kostova Z, Schaefer A et al. A genomic screen identifies Dsk2p and Rad23p as essential components of ER-associated degradation. EMBO Rep 2004; 5(7):692–697.PubMedGoogle Scholar
  65. 65.
    Richly H, Rape M, Braun S et al. A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 2005; 120(1):73–84.PubMedGoogle Scholar
  66. 66.
    Crosas B, Hanna J, Kirkpatrick DS et al. Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities. Cell 2006; 127(7):1401–1413.PubMedGoogle Scholar
  67. 67.
    Kohlmann S, Schafer A, Wolf DH. Ubiquitin ligase Hul5 is required for fragment-specific substrate degradation in endoplasmic reticulum-associated degradation. J Biol Chem 2008; 283(24):16374–16383.PubMedGoogle Scholar
  68. 68.
    Huyer G, Piluek WF, Fansler Z et al. Distinct machinery is required in Saccharomyces cerevisiae for the endoplasmic reticulum-associated degradation of a multispanning membrane protein and a soluble luminal protein. J Biol Chem 2004; 279(37):38369–38378.PubMedGoogle Scholar
  69. 69.
    Vashist S, Ng DT. Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control. J Cell Biol 2004; 165(1):41–52.PubMedGoogle Scholar
  70. 70.
    Swanson R, Locher M, Hochstrasser M. A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matalpha2 repressor degradation. Genes Dev 2001; 15(20):2660–2674.PubMedGoogle Scholar
  71. 71.
    Kreft SG, Wang L, Hochstrasser M. Membrane topology of the yeast endoplasmic reticulum-localized ubiquitin ligase Doa10 and comparison with its human ortholog TE B4 (MARCH-VI). J Biol Chem 2006; 281(8):4646–4653.PubMedGoogle Scholar
  72. 72.
    Gnann A, Riordan JR, Wolf DH. Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDE M and the Cdc48 protein complex in yeast. Mol Biol Cell 2004; 15(9):4125–4135.PubMedGoogle Scholar
  73. 73.
    Ravid T, Kreft SG, Hochstrasser M. Membrane and soluble substrates of the Doa10 ubiquitin ligase are degraded by distinct pathways. EMBO J 2006; 25(3):533–543.PubMedGoogle Scholar
  74. 74.
    Metzger MB, Maurer MJ, Dancy BM et al. Degradation of a cytosolic protein requires endoplasmic reticulum-associated degradation machinery. J Biol Chem 2008; 283(47):32302–32316.PubMedGoogle Scholar
  75. 75.
    Nadav E, Shmueli A, Barr H et al. A novel mammalian endoplasmic reticulum ubiquitin ligase homologous to the yeast Hrd1. Biochem Biophys Res Commun 2003; 303(1):91–97.PubMedGoogle Scholar
  76. 76.
    Kikkert M, Doolman R, Dai M et al. Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum. J Biol Chem 2004; 279(5):3525–3534.PubMedGoogle Scholar
  77. 77.
    Cattaneo M, Otsu M, Fagioli C et al. SEL1L and HRD1 are involved in the degradation of unassembled secretory Ig-mu chains. J Cell Physiol 2008; 215(3):794–802.PubMedGoogle Scholar
  78. 78.
    Okuda-Shimizu Y, Hendershot LM. Characterization of an ERAD pathway for nonglycosylated BiP substrates, which require Herp. Mol Cell 2007; 28(4):544–554.PubMedGoogle Scholar
  79. 79.
    Arteaga MF, Wang L, Ravid T et al. An amphipathic helix targets serum and glucocorticoid-induced kinase 1 to the endoplasmic reticulum-associated ubiquitin-conjugation machinery. Proc Natl Acad Sci USA 2006; 103(30):11178–11183.PubMedGoogle Scholar
  80. 80.
    Yamasaki S, Yagishita N, Sasaki T et al. Cytoplasmic destruction of p53 by the endoplasmic reticulum-resident ubiquitin ligase’ synoviolin’. EMBO J 2007; 26(1):113–122.PubMedGoogle Scholar
  81. 81.
    Fang S, Ferrone M, Yang C et al. The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum. Proc Natl Acad Sci USA 2001; 98(25):14422–14427.PubMedGoogle Scholar
  82. 82.
    Chen B, Mariano J, Tsai YC et al. The activity of a human endoplasmic reticulum-associated degradation E3, gp78, requires its Cue domain, RING finger and an E2-binding site. Proc Natl Acad Sci USA 2006; 103(2):341–346.PubMedGoogle Scholar
  83. 83.
    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(6):829–840.PubMedGoogle Scholar
  84. 84.
    Shmueli A, Tsai YC, Yang M et al. Targeting of gp78 for ubiquitin-mediated proteasomal degradation by Hrd1: cross-talk between E3s in the endoplasmic reticulum. Biochem Biophys Res Commun 2009; 390(3):758–762.PubMedGoogle Scholar
  85. 85.
    Ballar P, Ors AU, Yang H et al. Differential regulation of CFTRDeltaF508 degradation by ubiquitin ligases gp78 and Hrd1. Int J Biochem Cell Biol 2009; 42(1):167–173.PubMedGoogle Scholar
  86. 86.
    Hassink G, Kikkert M, van Voorden S et al. TE B4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum. Biochem J 2005; 388(Pt 2):647–655.PubMedGoogle Scholar
  87. 87.
    Zavacki AM, Arrojo EDR, Freitas BC et al. The E3 ubiquitin ligase TE B4 mediates degradation of type 2 iodothyronine deiodinase. Mol Cell Biol 2009; 29(19):5339–5347.PubMedGoogle Scholar
  88. 88.
    Dentice M, Bandyopadhyay A, Gereben B et al. The Hedgehog-inducible ubiquitin ligase subunit WSB-1 modulates thyroid hormone activation and PTHrP secretion in the developing growth plate. Nat Cell Biol 2005; 7(7):698–705.PubMedGoogle Scholar
  89. 89.
    Gemmill RM, West JD, Boldog F et al. The hereditary renal cell carcinoma 3; 8 translocation fuses FHIT to a patched-related gene, TRC8. Proc Natl Acad Sci USA 1998; 95(16):9572–9577.PubMedGoogle Scholar
  90. 90.
    Irisawa M, Inoue J, Ozawa N et al. 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 2009; 284(42):28995–29004.PubMedGoogle Scholar
  91. 91.
    Stagg HR, Thomas M, van den Boomen D et al. The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER. J Cell Biol 2009; 186(5):685–692.PubMedGoogle Scholar
  92. 92.
    Wiertz EJ, Tortorella D, Bogyo M et al. Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 1996; 384(6608):432–438.PubMedGoogle Scholar
  93. 93.
    Lerner M, Corcoran M, Cepeda D et al. The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase involved in ERAD. Mol Biol Cell 2007; 18(5):1670–1682.PubMedGoogle Scholar
  94. 94.
    Morito D, Hirao K, Oda Y et al. Gp78 cooperates with RMA1 in endoplasmic reticulum-associated degradation of CFTRDeltaF508. Mol Biol Cell 2008; 19(4):1328–1336.PubMedGoogle Scholar
  95. 95.
    Imai Y, Soda M, Inoue H et al. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 2001; 105(7):891–902.PubMedGoogle Scholar
  96. 96.
    Omura T, Kaneko M, Okuma Y et al. A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin. J Neurochem 2006; 99(6):1456–1469.PubMedGoogle Scholar
  97. 97.
    Fewell SW, Travers KJ, Weissman JS et al. The action of molecular chaperones in the early secretory pathway. Annu Rev Genet 2001; 35:149–191.PubMedGoogle Scholar
  98. 98.
    Taxis C, Hitt R, Park SH et al. Use of modular substrates demonstrates mechanistic diversity and reveals differences in chaperone requirement of ERAD. J Biol Chem 2003; 278(38):35903–35913.PubMedGoogle Scholar
  99. 99.
    Nishikawa SI, Fewell SW, Kato Y et al. Molecular chaperones in the yeast endoplasmic reticulum maintain the solubility of proteins for retrotranslocation and degradation. J Cell Biol 2001; 153(5):1061–1070.PubMedGoogle Scholar
  100. 100.
    Ruddock LW, Molinari M. N-glycan processing in ER quality control. J Cell Sci 2006; 119(Pt 21):4373–4380.PubMedGoogle Scholar
  101. 101.
    Wang X, Ye Y, Lencer W et al. The viral E3 ubiquitin ligase mK3 uses the Derlin/p97 endoplasmic reticulum-associated degradation pathway to mediate down-regulation of major histocompatibility complex class I proteins. J Biol Chem 2006; 281(13):8636–8644.PubMedGoogle Scholar
  102. 102.
    Oh RS, Bai X, Rommens JM. Human homologs of Ubc6p ubiquitin-conjugating enzyme and phosphorylation of HsUbc6e in response to endoplasmic reticulum stress. J Biol Chem 2006; 281(30):21480–21490.PubMedGoogle Scholar
  103. 103.
    Tiwari S, Weissman AM. Endoplasmic reticulum (ER)-associated degradation of T-cell receptor subunits. Involvement of ER-associated ubiquitin-conjugating enzymes (E2s). J Biol Chem 2001; 276(19):16193–16200.PubMedGoogle Scholar
  104. 104.
    Schuberth C, Buchberger A. UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97. Cell Mol Life Sci 2008; 65(15):2360–2371.PubMedGoogle Scholar
  105. 105.
    Kothe M, Ye Y, Wagner JS et al. Role of p97 AAA-ATPase in the retrotranslocation of the cholera toxin A1 chain, a non-ubiquitinated substrate. J Biol Chem 2005; 280(30):28127–28132.PubMedGoogle Scholar
  106. 106.
    Ye Y, Meyer HH, Rapoport TA. Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of non-ubiquitinated polypeptide segments and polyubiquitin chains. J Cell Biol 2003; 162(1):71–84.PubMedGoogle Scholar
  107. 107.
    Meyer HH, Wang Y, Warren G. Direct binding of ubiquitin conjugates by the mammalian p97 adaptor complexes, p47 and Ufd1-Npl4. EMBO J 2002; 21(21):5645–5652.PubMedGoogle Scholar
  108. 108.
    Kleijnen MF, Alarcon RM, Howley PM. The ubiquitin-associated domain of hPLIC-2 interacts with the proteasome. Mol Biol Cell 2003; 14(9):3868–3875.PubMedGoogle Scholar
  109. 109.
    Chen L, Madura K. Evidence for distinct functions for human DNA repair factors hHR23A and hHR23B. FEBS Lett 2006; 580(14):3401–3408.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Frederik Eisele
    • 2
  • Antje Schäfer
    • 1
  • Dieter H. Wolf
    • 2
  1. 1.Rudolf Virchow Zentrum für Experimentelle BiomedizinUniversität WürzburgWürzburgGermany
  2. 2.Institut für BiochemieUniversität StuttgartStuttgartGermany

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