ER-associated Degradation and Its Involvement in Human Disease: Insights from Yeast

Part of the Protein Reviews book series (PRON, volume 13)


Endoplasmic reticulum-associated protein degradation (ERAD) is a cellular process that targets short-lived resident proteins and aberrant secretory proteins to the proteasome for degradation. ERAD is essential for maintaining the homeostasis of the secretory pathway, as the retention of misfolded proteins in the ER can lead to several diseases. The budding yeast Saccharomyces cerevisiae has been used as a model organism for dissecting the molecular components of the ERAD pathway. This review describes the multi-subunit protein machineries in the ER membrane that are involved in the recognition of misfolded proteins, their ubiquitylation, and their retro-translocation to the cytosol and delivery to the proteasome. Most of the yeast components are conserved in humans and the analysis of the function in ERAD of the yeast counterparts has been crucial in elucidating the mechanisms responsible for human disorders.


Endoplasmic Reticulum Amyotrophic Lateral Sclerosis Endoplasmic Reticulum Stress Unfold Protein Response Misfolded Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We apologize to those whose work we were unable to cite due to space constraints. N. C is supported by a grant from the Fonds pour la formation à la Recherche dans l’Industrie et dans l’Agriculture (F.R.I.A.).


  1. Ahner, A., and Brodsky, J.L. (2004). Checkpoints in ER-associated degradation: excuse me, which way to the proteasome? Trends Cell Biol. 14:474–478.PubMedCrossRefGoogle Scholar
  2. Alam, S.L., Sun, J., Payne, M., et al. (2004). Ubiquitin interactions of NZF zinc fingers. EMBO J. 23:1411–1421.PubMedCrossRefGoogle Scholar
  3. Alrefai, W.A., and Gill, R.K. (2007). Bile acid transporters: structure, function, regulation and pathophysiological implications. Pharm. Res. 24:1803–1823.PubMedCrossRefGoogle Scholar
  4. Amano, T., Yamasaki, S., Yagishita, N., et al. (2003). Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy. Genes Dev. 17:2436–2449.PubMedCrossRefGoogle Scholar
  5. Anelli, T., and Sitia, R. (2008). Protein quality control in the early secretory pathway. EMBO J. 27:315–327.PubMedCrossRefGoogle Scholar
  6. Arteaga, M.F., Wang, L., Ravid, T., et al. (2006). An amphipathic helix targets serum and glucocorticoid-induced kinase 1 to the endoplasmic reticulum-associated ubiquitin-conjugation machinery. Proc. Natl. Acad. Sci. USA. 103:11178–11183.PubMedCrossRefGoogle Scholar
  7. Balzi, E., Wang, M., Leterme, S., et al. (1994). PDR5, a novel yeast multidrug resistance conferring transporter controlled by the transcription regulator PDR1. J. Biol. Chem. 269:2206–2214.PubMedGoogle Scholar
  8. Bays, N.W., Gardner, R.G., Seelig, L.P., et al. (2001a). Hrd1p/Der3p is a membrane-anchored ubiquitin ligase required for ER-associated degradation. Nat. Cell Biol. 3:24–29.PubMedCrossRefGoogle Scholar
  9. Bays, N.W., Wilhovsky, S.K., Goradia, A., et al. (2001b). HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol. Biol. Cell 12:4114–4128.PubMedGoogle Scholar
  10. Bernales, S., Schuck, S., Walter, P. (2007). ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3:285–287.PubMedGoogle Scholar
  11. Bernardi, K.M., Forster, M.L., Lencer, W.I. et al. (2008). Derlin-1 facilitates the retro-translocation of cholera toxin. Mol. Biol. Cell 19:877–884.PubMedCrossRefGoogle Scholar
  12. Bhamidipati, A., Denic, V., Quan, E.M. et al. (2005). Exploration of the topological requirements of ERAD identifies Yos9p as a lectin sensor of misfolded glycoproteins in the ER lumen. Mol. Cell 19:741–751.PubMedCrossRefGoogle Scholar
  13. Biederer, T., Volkwein, C., Sommer, T. (1997). Role of Cue1p in ubiquitination and degradation at the ER surface. Science 278:1806–1809.PubMedCrossRefGoogle Scholar
  14. Bissinger, P.H., and Kuchler, K. (1994). Molecular cloning and expression of the Saccharomyces cerevisiae STS1 gene product. A yeast ABC transporter conferring mycotoxin resistance. J. Biol. Chem. 269:4180–4186.PubMedGoogle Scholar
  15. Braun, S., Matuschewski, K., Rape, M., et al. (2002). Role of the ubiquitin-selective CDC48 (UFD1/NPL4) chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J. 21:615–621.PubMedCrossRefGoogle Scholar
  16. Brodsky, J.L. (1996). Post-translational protein translocation: not all hsc70s are created equal. Trends Biochem. Sci. 21:122–126.PubMedGoogle Scholar
  17. Bruderer, R.M., Brasseur, C., Meyer, H.H. (2004). The AAA ATPase p97/VCP interacts with its alternative co-factors, Ufd1-Npl4 and p47, through a common bipartite binding mechanism. J. Biol. Chem. 279:49609–49616.PubMedCrossRefGoogle Scholar
  18. Bukau, B., Weissman, J., Horwich, A. (2006). Molecular chaperones and protein quality control. Cell 125:443–451.PubMedCrossRefGoogle Scholar
  19. Buschhorn, B.A., Kostova, Z., Medicherla, B. et al. (2004). A genome-wide screen identifies Yos9p as essential for ER-associated degradation of glycoproteins. FEBS Lett. 577:422–426.PubMedCrossRefGoogle Scholar
  20. Byrd, J.C., Tarentino, A.L., Maley, F., et al. (1982). Glycoprotein synthesis in yeast. Identification of Man8GlcNAc2 as an essential intermediate in oligosaccharide processing. J. Biol. Chem. 257:14657–14666.PubMedGoogle Scholar
  21. Carvalho, P., Goder, V., Rapoport, T.A. (2006). Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126:361–373.PubMedCrossRefGoogle Scholar
  22. Chapman, R., Sidrauski, C., Walter, P. (1998). Intracellular signaling from the endoplasmic reticulum to the nucleus. Annu. Rev. Cell Dev. Biol. 14:459–485.PubMedCrossRefGoogle Scholar
  23. Chen, L., and Madura, K. (2002). Rad23 promotes the targeting of proteolytic substrates to the proteasome. Mol. Cell Biol. 22:4902–4913.PubMedCrossRefGoogle Scholar
  24. Chen, S.Y., Bhargava, A., Mastroberardino, L., et al. (1999). Epithelial sodium channel regulated by aldosterone-induced protein sgk. Proc. Natl. Acad. Sci. USA. 96:2514–2519.PubMedCrossRefGoogle Scholar
  25. Clerc, S., Hirsch, C., Oggier, D.M., et al. (2009). Htm1 protein generates the N-glycan signal for glycoprotein degradation in the endoplasmic reticulum. J. Cell Biol. 184:159–172.PubMedCrossRefGoogle Scholar
  26. Cox, J.S., and Walter, P. (1996). A novel mechanism for regulating activity of a transcription factor that controls the unfolded protein response. Cell 87:391–404.PubMedCrossRefGoogle Scholar
  27. de Kerchove d’Exaerde, A., Supply, P., Dufour, J.P., et al. (1995). Functional complementation of a null mutation of the yeast Saccharomyces cerevisiae plasma membrane H(+)-ATPase by a plant H(+)-ATPase gene. J. Biol. Chem. 270:23828–23837.PubMedCrossRefGoogle Scholar
  28. Deak, P.M., and Wolf, D.H. (2001). Membrane topology and function of Der3/Hrd1p as a ubiquitin-protein ligase (E3) involved in endoplasmic reticulum degradation. J. Biol. Chem. 276:10663–10669.PubMedCrossRefGoogle Scholar
  29. Decottignies, A., Evain, A., Ghislain, M. (2004). Binding of Cdc48p to a ubiquitin-related UBX domain from novel yeast proteins involved in intracellular proteolysis and sporulation. Yeast 21:127–139.PubMedCrossRefGoogle Scholar
  30. De LaBarre, B., and Brunger, A.T. (2003). Complete structure of p97/valosin-containing protein reveals communication between nucleotide domains. Nat. Struct. Biol. 10:856–863.CrossRefGoogle Scholar
  31. Denic, V., Quan, E.M., Weissman, J.S. (2006). A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell 126:349–359.PubMedCrossRefGoogle Scholar
  32. Dolinski, K., Muir, S., Cardenas, M., et al. (1997). All cyclophilins and FK506 binding proteins are, individually and collectively, dispensable for viability in Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA. 94:13093–13098.PubMedCrossRefGoogle Scholar
  33. Dreveny, I., Kondo, H., Uchiyama, K., et al. (2004). Structural basis of the interaction between the AAA ATPase p97/VCP and its adaptor protein p47. EMBO J. 23:1030–1039.PubMedCrossRefGoogle Scholar
  34. Egner, R., Rosenthal, F.E., Kralli, A., Sanglard, D. et al. (1998). Genetic separation of FK506 susceptibility and drug transport in the yeast Pdr5 ATP-binding cassette multidrug resistance transporter. Mol. Biol. Cell 9:523–543.PubMedGoogle Scholar
  35. Ellgaard, L., and Helenius, A. (2003). Quality control in the endoplasmic reticulum. Nat. Rev. Mol. Cell Biol. 4:181–191.PubMedCrossRefGoogle Scholar
  36. Elsasser, S., Gali, R.R., Schwickart, M., et al. (2002). Proteasome subunit Rpn1 binds ubiquitin-like protein domains. Nat. Cell Biol. 4:725–730.PubMedCrossRefGoogle Scholar
  37. Fassio, A., and Sitia, R. (2002). Formation, isomerisation and reduction of disulphide bonds during protein quality control in the endoplasmic reticulum. Histochem. Cell Biol. 117:151–157.PubMedCrossRefGoogle Scholar
  38. Finger, A., Knop, M., Wolf, D.H. (1993). Analysis of two mutated vacuolar proteins reveals a degradation pathway in the endoplasmic reticulum or a related compartment of yeast. Eur. J. Biochem. 218:565–574.PubMedCrossRefGoogle Scholar
  39. Friedlander, R., Jarosch, E., Urban, J., et al. (2000). A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nat. Cell Biol. 2:379–384.PubMedCrossRefGoogle Scholar
  40. Frohlich, K.U., Fries, H.W., Rudiger, M., et al. (1991). Yeast cell cycle protein CDC48p shows full-length homology to the mammalian protein VCP and is a member of a protein family involved in secretion, peroxisome formation, and gene expression. J. Cell Biol. 114:443–453.PubMedCrossRefGoogle Scholar
  41. Funakoshi, M., Sasaki, T., Nishimoto, T. et al. (2002). Budding yeast Dsk2p is a polyubiquitin-binding protein that can interact with the proteasome. Proc. Natl. Acad. Sci. USA. 99:745–750.PubMedCrossRefGoogle Scholar
  42. Gardner, R.G., Swarbrick, G.M., Bays, N.W., et al. (2000). Endoplasmic reticulum degradation requires lumen to cytosol signaling. Transmembrane control of Hrd1p by Hrd3p. J. Cell Biol. 151:69–82.CrossRefGoogle Scholar
  43. Gauss, R., Jarosch, E., Sommer, T. et al. (2006a). A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery. Nat. Cell Biol. 8:849–854.PubMedCrossRefGoogle Scholar
  44. Gauss, R., Sommer, T., Jarosch, E. (2006b). The Hrd1p ligase complex forms a linchpin between ER-lumenal substrate selection and Cdc48p recruitment. EMBO J. 25:1827–1835.PubMedCrossRefGoogle Scholar
  45. Gnann, A., Riordan, J.R., Wolf, D.H. (2004). Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast. Mol. Biol. Cell 15:4125–4135.PubMedCrossRefGoogle Scholar
  46. Gross, E., Sevier, C.S., Heldman, N., et al. (2006). Generating disulfides enzymatically: reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p. Proc. Natl. Acad. Sci. USA. 103: 299–304.PubMedCrossRefGoogle Scholar
  47. Hampton, R.Y., Gardner, R.G., 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 7:2029–2044.PubMedGoogle Scholar
  48. Hampton, R.Y. (2002). ER-associated degradation in protein quality control and cellular regulation. Curr. Opin. Cell Biol. 14:476–482.PubMedCrossRefGoogle Scholar
  49. Hampton, R.Y. (2003). IRE1: a role in UPREgulation of ER degradation. Dev. Cell 4:144–146.PubMedCrossRefGoogle Scholar
  50. Harris, S.L., Na, S., Zhu, X., et al. (1994). Dominant lethal mutations in the plasma membrane H(+)-ATPase gene of Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA. 91:10531–10535.PubMedCrossRefGoogle Scholar
  51. Helenius, A., and Aebi, M. (2004). Roles of N-linked glycans in the endoplasmic reticulum. Annu. Rev. Biochem. 73:1019–1049.PubMedCrossRefGoogle Scholar
  52. Hiller, M.M., Finger, A., Schweiger, M., et al. (1996). ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science 273:1725–1728.PubMedCrossRefGoogle Scholar
  53. Hirao, K., Natsuka, Y., Tamura, T., et al. (2006). EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming. J. Biol. Chem. 281:9650–9658.PubMedCrossRefGoogle Scholar
  54. Hirsch, C., Misaghi, S., Blom, D., et al. (2004). Yeast N-glycanase distinguishes between native and non-native glycoproteins. EMBO Rep. 5:201–206.PubMedCrossRefGoogle Scholar
  55. Hirsch, C., Gauss, R., Sommer, T. (2006). Coping with stress: cellular relaxation techniques. Trends Cell Biol. 16:657–663.PubMedCrossRefGoogle Scholar
  56. Hitchcock, A.L., Krebber, H., Frietze, S., et al. (2001). The conserved npl4 protein complex mediates proteasome-dependent membrane-bound transcription factor activation. Mol. Biol. Cell 12:3226–3241.PubMedGoogle Scholar
  57. Hitt, R., and Wolf, D.H. (2004a). DER7, encoding alpha-glucosidase I is essential for degradation of malfolded glycoproteins of the endoplasmic reticulum. FEMS Yeast Res. 4:815–820.PubMedCrossRefGoogle Scholar
  58. Hitt, R., and Wolf, D.H. (2004b). Der1p, a protein required for degradation of malfolded soluble proteins of the endoplasmic reticulum: topology and Der1-like proteins. FEMS Yeast Res. 4:721–729.PubMedCrossRefGoogle Scholar
  59. Hiyama, H., Yokoi, M., Masutani, C., et al. (1999). Interaction of hHR23 with S5a. The ubiquitin-like domain of hHR23 mediates interaction with S5a subunit of 26 S proteasome. J. Biol. Chem. 274:28019–28025.PubMedCrossRefGoogle Scholar
  60. Hoppe, T. (2005). Multiubiquitylation by E4 enzymes: ‘one size’ doesn’t fit all. Trends Biochem. Sci. 30:183–187.PubMedCrossRefGoogle Scholar
  61. Hosokawa, N., Wada, I., Hasegawa, K., et al. (2001). A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation. EMBO Rep. 2:415–422.PubMedGoogle Scholar
  62. Huyer, G., Longsworth, G.L., Mason, D.L., et al. (2004a). A striking quality control subcompartment in Saccharomyces cerevisiae: the endoplasmic reticulum-associated compartment. Mol. Biol. Cell 15:908–921.PubMedCrossRefGoogle Scholar
  63. Huyer, G., Piluek, W.F., Fansler, Z., et al. (2004b). 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. 279:38369–38378.PubMedCrossRefGoogle Scholar
  64. Imai, Y., Soda, M., Inoue, H., et al. (2001). An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105:891–902.PubMedCrossRefGoogle Scholar
  65. Imai, Y., Soda, M., Hatakeyama, S., et al. (2002). CHIP is associated with Parkin, a gene responsible for familial Parkinson’s disease, and enhances its ubiquitin ligase activity. Mol. Cell 10:55–67.PubMedCrossRefGoogle Scholar
  66. Jakob, C.A., Burda, P., Roth, J., et al. (1998). Degradation of misfolded endoplasmic reticulum glycoproteins in Saccharomyces cerevisiae is determined by a specific oligosaccharide structure. J. Cell Biol. 142:1223–1233.PubMedCrossRefGoogle Scholar
  67. Jakob, C.A., Bodmer, D., Spirig, U., et al. (2001). Htm1p, a mannosidase-like protein, is involved in glycoprotein degradation in yeast. EMBO Rep. 2:423–430.PubMedGoogle Scholar
  68. Jarosch, E., Taxis, C., Volkwein, C., et al. (2002). Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat. Cell Biol. 4:134–139.PubMedCrossRefGoogle Scholar
  69. Kaganovich, D., Kopito, R., Frydman, J. (2008). Misfolded proteins partition between two distinct quality control compartments. Nature 454:1088–1095.PubMedCrossRefGoogle Scholar
  70. Kanehara, K., Kawaguchi, S., Ng D.T. (2007). The EDEM and Yos9p families of lectin-like ERAD factors. Semin. Cell Dev. Biol. 18:743–750.PubMedCrossRefGoogle Scholar
  71. Kikkert, M., Doolman, R., Dai, M., et al. (2004). Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum. J. Biol. Chem. 279:3525–3534.PubMedCrossRefGoogle Scholar
  72. Kim, I., Mi, K., Rao, H. (2004). Multiple interactions of rad23 suggest a mechanism for ubiquitylated substrate delivery important in proteolysis. Mol. Biol. Cell 15:3357–3365.PubMedCrossRefGoogle Scholar
  73. Kim, W., Spear, E.D., Ng, D.T. (2005). Yos9p detects and targets misfolded glycoproteins for ER-associated degradation. Mol. Cell 19:753–764.PubMedCrossRefGoogle Scholar
  74. Klionsky, D.J. (2007). Autophagy: from phenomenology to molecular understanding in less than a decade. Nat. Rev. Mol. Cell. Biol. 8:931–937.PubMedCrossRefGoogle Scholar
  75. Knop, M., Finger, A., Braun, T., et al. (1996). Der1, a novel protein specifically required for endoplasmic reticulum degradation in yeast. EMBO J. 15:753–763.PubMedGoogle Scholar
  76. Koegl, M., Hoppe, T., Schlenker, S., et al. (1999). A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly. Cell 96:635–644.PubMedCrossRefGoogle Scholar
  77. Kolling, R., and Hollenberg, C.P. (1994). The ABC-transporter Ste6 accumulates in the plasma membrane in a ubiquitinated form in endocytosis mutants. EMBO J. 13:3261–3271.PubMedGoogle Scholar
  78. Kopito, R.R. (1997). ER quality control: the cytoplasmic connection. Cell 88:427–430.PubMedCrossRefGoogle Scholar
  79. Kostova, Z., and Wolf, D.H. (2003). For whom the bell tolls: protein quality control of the endoplasmic reticulum and the ubiquitin-proteasome connection. EMBO J. 22:2309–2317.PubMedCrossRefGoogle Scholar
  80. Kozutsumi, Y., Normington, K., Press, E., et al. (1989). Identification of immunoglobulin heavy chain binding protein as glucose-regulated protein 78 on the basis of amino acid sequence, immunological cross-reactivity, and functional activity. J. Cell Sci. Suppl. 11:115–137.PubMedGoogle Scholar
  81. Krebs, M.P., Noorwez, S.M., Malhotra, R., et al. (2004). Quality control of integral membrane proteins. Trends Biochem. Sci. 29:648–655.PubMedCrossRefGoogle Scholar
  82. Kreft, S.G., Wang, L., Hochstrasser, M. (2006). Membrane topology of the yeast endoplasmic reticulum-localized ubiquitin ligase Doa10 and comparison with its human ortholog TEB4 (MARCH-VI). J. Biol. Chem. 281:4646–4653.PubMedCrossRefGoogle Scholar
  83. Lenk, U., Yu, H., Walter, J., et al. (2002). A role for mammalian Ubc6 homologues in ER-associated protein degradation. J. Cell Sci. 115:3007–3014.PubMedGoogle Scholar
  84. Levine, B., and Klionsky, D.J. (2004). Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev. Cell 6:463–477.PubMedCrossRefGoogle Scholar
  85. Lilley, B.N., and Ploegh, H.L. (2004). A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429:834–840.PubMedCrossRefGoogle Scholar
  86. Loayza, D., Tam, A., Schmidt, W.K., et al. (1998). Ste6p mutants defective in exit from the endoplasmic reticulum (ER) reveal aspects of an ER quality control pathway in Saccharomyces cerevisiae. Mol. Biol. Cell 9:2767–2784.PubMedGoogle Scholar
  87. Madsen, L., Schulze, A., Seeger, M., et al. (2007). Ubiquitin domain proteins in disease. BMC Biochem. 8(Suppl 1): S1.PubMedCrossRefGoogle Scholar
  88. Mah, A.L., Perry, G., Smith, M.A., et al. (2000). Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. J. Cell Biol. 151:847–862.PubMedCrossRefGoogle Scholar
  89. Mast, S.W., Diekman, K., Karaveg, K., et al. (2005). Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins. Glycobiology 15:421–436.PubMedCrossRefGoogle Scholar
  90. Mazon, M.J., Eraso, P., Portillo, F. (2007). Efficient degradation of misfolded mutant Pma1 by endoplasmic reticulum-associated degradation requires Atg19 and the Cvt/autophagy pathway. Mol. Microbiol. 63:1069–1077.PubMedCrossRefGoogle Scholar
  91. McCracken, A.A., and Brodsky, J.L. (1996). Assembly of ER-associated protein degradation in vitro: dependence on cytosol, calnexin, and ATP. J. Cell Biol. 132:291–298.PubMedCrossRefGoogle Scholar
  92. McCracken, A.A., and Brodsky, J.L. (2003). Evolving questions and paradigm shifts in endoplasmic-reticulum-associated degradation (ERAD). Bioessays 25:868–877.PubMedCrossRefGoogle Scholar
  93. McGrath, J.P., and Varshavsky, A. (1989). The yeast STE6 gene encodes a homologue of the mammalian multidrug resistance P-glycoprotein. Nature 340:400–404.PubMedCrossRefGoogle Scholar
  94. Meacham, G.C., Patterson, C., Zhang, W., et al. (2001). The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat. Cell Biol. 3:100–105.PubMedCrossRefGoogle Scholar
  95. Medicherla, B., Kostova, Z., Schaefer, A., et al. (2004). A genomic screen identifies Dsk2p and Rad23p as essential components of ER-associated degradation. EMBO Rep. 5:692–697.PubMedCrossRefGoogle Scholar
  96. Metzger, M.B., Maurer, M.J., Dancy, B.M., et al. (2008). Degradation of a cytosolic protein requires endoplasmic reticulum-associated degradation machinery. J. Biol. Chem. 283:32302–32316.PubMedCrossRefGoogle Scholar
  97. Meusser, B., Hirsch, C., Jarosch, E., et al. (2005). ERAD: the long road to destruction. Nat. Cell Biol. 7:766–772.PubMedCrossRefGoogle Scholar
  98. Meyer, H.H., Shorter, J.G., Seemann, J., et al. (2000). A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. EMBO J. 19:2181–2192.PubMedCrossRefGoogle Scholar
  99. Molinari, M., Calanca, V., Galli, C., et al. (2003). Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle. Science 299:1397–1400.PubMedCrossRefGoogle Scholar
  100. Movsichoff, F., Castro, O.A., Parodi, A.J. (2005). Characterization of Schizosaccharomyces pombe ER alpha-mannosidase: a reevaluation of the role of the enzyme on ER-associated degradation. Mol. Biol. Cell 16:4714–4724.PubMedCrossRefGoogle Scholar
  101. Nadav, E., Shmueli, A., Barr, H., et al. (2003). A novel mammalian endoplasmic reticulum ubiquitin ligase homologous to the yeast Hrd1. Biochem. Biophys. Res. Commun. 303:91–97.PubMedCrossRefGoogle Scholar
  102. Nakamoto, R.K., Verjovski-Almeida, S., Allen, K.E., et al. (1998). Substitutions of aspartate 378 in the phosphorylation domain of the yeast PMA1 H + -ATPase disrupt protein folding and biogenesis. J. Biol. Chem. 273:7338–7344.PubMedCrossRefGoogle Scholar
  103. Nakatsukasa, K., Nishikawa, S., Hosokawa, N., et al. (2001). Mnl1p, an alpha-mannosidase-like protein in yeast Saccharomyces cerevisiae, is required for endoplasmic reticulum-associated degradation of glycoproteins. J. Biol. Chem. 276:8635–8638.PubMedCrossRefGoogle Scholar
  104. Nakatsukasa, K., and Brodsky, J.L. (2008). The recognition and retrotranslocation of misfolded proteins from the endoplasmic reticulum. Traffic 9:861–870.PubMedCrossRefGoogle Scholar
  105. Nakatsukasa, K., Huyer, G., Michaelis, S., et al. (2008). Dissecting the ER-associated degradation of a misfolded polytopic membrane protein. Cell 132:101–112.PubMedCrossRefGoogle Scholar
  106. Neuber, O., Jarosch, E., Volkwein, C., et al. (2005). Ubx2 links the Cdc48 complex to ER-associated protein degradation. Nat. Cell Biol. 7:993–998.PubMedCrossRefGoogle Scholar
  107. Nishikawa, S.I., Fewell, S.W., Kato, Y., et al. T (2001). Molecular chaperones in the yeast endoplasmic reticulum maintain the solubility of proteins for retrotranslocation and degradation. J. Cell Biol. 153:1061–1070PubMedCrossRefGoogle Scholar
  108. Nishitoh, H., Kadowaki, H., Nagai, A., et al. (2008). ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1. Genes Dev. 22:1451–1464.PubMedCrossRefGoogle Scholar
  109. Nita-Lazar, M., and Lennarz, W.J. (2005). Pkc1p modifies CPY* degradation in the ERAD pathway. Biochem. Biophys. Res. Commun. 332:357–361.PubMedCrossRefGoogle Scholar
  110. Norgaard, P., Westphal, V., Tachibana, C., et al. (2001). Functional differences in yeast protein disulfide isomerases. J. Cell Biol. 152:553–562.PubMedCrossRefGoogle Scholar
  111. Normington, K., Kohno, K., Kozutsumi, Y., et al. (1989). S. cerevisiae encodes an essential protein homologous in sequence and function to mammalian BiP. Cell 57:1223–1236.PubMedCrossRefGoogle Scholar
  112. Oda, Y., Hosokawa, N., Wada, I., et al. (2003). EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin. Science 299:1394–1397.PubMedCrossRefGoogle Scholar
  113. Omura, T., Kaneko, M., Okuma, Y., et al. (2006). A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin. J. Neurochem. 99:1456–1469.PubMedCrossRefGoogle Scholar
  114. Park, S, Isaacson, R., Kim, H.T., et al. (2005). Ufd1 exhibits the AAA-ATPase fold with two distinct ubiquitin interaction sites. Structure 13:995–1005.PubMedCrossRefGoogle Scholar
  115. Pilon, M., Schekman, R., Romisch, K. (1997). Sec61p mediates export of a misfolded secretory protein from the endoplasmic reticulum to the cytosol for degradation. EMBO J. 16:4540–4548.PubMedCrossRefGoogle Scholar
  116. Plemper, R.K., Bohmler, S., Bordallo, J., et al. (1997). Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation. Nature 388: 891–895.PubMedCrossRefGoogle Scholar
  117. Plemper, R.K., Egner, R., Kuchler, K., et al. (1998). Endoplasmic reticulum degradation of a mutated ATP-binding cassette transporter Pdr5 proceeds in a concerted action of Sec61 and the proteasome. J. Biol. Chem. 273: 32848–32856.PubMedCrossRefGoogle Scholar
  118. Plemper, R.K., Bordallo, J., Deak, P.M., et al. (1999). Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro-translocation complex mediating protein transport for ER degradation. J. Cell Sci. 112 (Pt 22):4123–4134.PubMedGoogle Scholar
  119. Plemper, R.K., and Wolf, D.H. (1999). Endoplasmic reticulum degradation. Reverse protein transport and its end in the proteasome. Mol. Biol. Rep. 26:125–130.PubMedCrossRefGoogle Scholar
  120. Rabinovich, E., Kerem, A., Frohlich, K.U., et al. (2002). AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol. Cell Biol. 22:626–634.PubMedCrossRefGoogle Scholar
  121. Rape, M., Hoppe, T., Gorr, I., et al. (2001). Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48 (UFD1/NPL4), a ubiquitin-selective chaperone. Cell 107:667–677.PubMedCrossRefGoogle Scholar
  122. Ravid, T., Kreft, S.G., Hochstrasser, M. (2006). Membrane and soluble substrates of the Doa10 ubiquitin ligase are degraded by distinct pathways. EMBO J. 25:533–543.PubMedCrossRefGoogle Scholar
  123. Richly, H., Rape, M., Braun, S., et al. (2005). A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 120:73–84.PubMedCrossRefGoogle Scholar
  124. Romisch, K. (1999). Surfing the Sec61 channel: bidirectional protein translocation across the ER membrane. J. Cell Sci. 112 (Pt 23):4185–4191.PubMedGoogle Scholar
  125. Ron, D., and Walter, P. (2007). Signal integration in the endoplasmic reticulum unfolded protein response. Nat. Rev. Mol. Cell. Biol. 8:519–529.PubMedCrossRefGoogle Scholar
  126. Rose, M.D., Misra, L.M., Vogel, J.P. (1989). KAR2, a karyogamy gene, is the yeast homolog of the mammalian BiP/GRP78 gene. Cell 57:1211–1221.PubMedCrossRefGoogle Scholar
  127. Rumpf, S., and Jentsch, S. (2006). Functional division of substrate processing cofactors of the ubiquitin-selective Cdc48 chaperone. Mol. Cell 21:261–269.PubMedCrossRefGoogle Scholar
  128. Sai, X., Kawamura, Y., Kokame, K., et al. (2002). Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein. J. Biol. Chem. 277:12915–12920.PubMedCrossRefGoogle Scholar
  129. Saris, N., Holkeri, H., Craven, R.A., et al. (1997). The Hsp70 homologue Lhs1p is involved in a novel function of the yeast endoplasmic reticulum, refolding and stabilization of heat-denatured protein aggregates. J. Cell Biol. 137:813–824.PubMedCrossRefGoogle Scholar
  130. Sato, B.K., and Hampton, R.Y. (2006). Yeast Derlin Dfm1 interacts with Cdc48 and functions in ER homeostasis. Yeast 23:1053–1064.PubMedCrossRefGoogle Scholar
  131. Schuberth, C., Richly, H., Rumpf, S., et al. (2004). Shp1 and Ubx2 are adaptors of Cdc48 involved in ubiquitin-dependent protein degradation. EMBO Rep. 5:818–824.PubMedCrossRefGoogle Scholar
  132. Schwieger, I., Lautz, K., Krause, E., et al. (2008). Derlin-1 and p97/valosin-containing protein mediate the endoplasmic reticulum-associated degradation of human V2 vasopressin receptors. Mol. Pharmacol. 73:697–708.PubMedCrossRefGoogle Scholar
  133. Scott, D.C., and Schekman, R. (2008). Role of Sec61p in the ER-associated degradation of short-lived transmembrane proteins. J. Cell Biol. 181:1095–1105.PubMedCrossRefGoogle Scholar
  134. Serrano, R., Kielland-Brandt, M.C., Fink, G.R. (1986). Yeast plasma membrane ATPase is essential for growth and has homology with (Na+, K+), K + - and Ca2+-ATPases. Nature 319:689–693.PubMedCrossRefGoogle Scholar
  135. Shamu, C.E., Cox, J.S., Walter, P. (1994). The unfolded-protein-response pathway in yeast. Trends Cell Biol. 4:56–60.PubMedCrossRefGoogle Scholar
  136. Shamu, C.E., and Walter, P. (1996). Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus. EMBO J. 15:3028–3039.PubMedGoogle Scholar
  137. Sidrauski, C., Chapman, R., Walter, P. (1998). The unfolded protein response: an intracellular signalling pathway with many surprising features. Trends Cell Biol. 8:245–249.PubMedCrossRefGoogle Scholar
  138. Sitia, R., and Braakman, I. (2003). Quality control in the endoplasmic reticulum protein factory. Nature 426:891–894.PubMedCrossRefGoogle Scholar
  139. Sommer, T., and Jentsch, S. (1993). A protein translocation defect linked to ubiquitin conjugation at the endoplasmic reticulum. Nature 365:176–179.PubMedCrossRefGoogle Scholar
  140. Song, Y., Sata, J., Saito, A., et al. (2001). Effects of calnexin deletion in Saccharomyces cerevisiae on the secretion of glycosylated lysozymes. J. Biochem. 130:757–764.PubMedCrossRefGoogle Scholar
  141. Spear, E.D., and Ng, D.T. (2005). Single, context-specific glycans can target misfolded glycoproteins for ER-associated degradation. J. Cell Biol. 169:73–82.PubMedCrossRefGoogle Scholar
  142. Staub, O., and Rotin, D. (2006). Role of ubiquitylation in cellular membrane transport. Physiol. Rev. 86:669–707.PubMedCrossRefGoogle Scholar
  143. Supply, P., Wach, A., Thines-Sempoux, D., et al. (1993). Proliferation of intracellular structures upon overexpression of the PMA2 ATPase in Saccharomyces cerevisiae. J. Biol. Chem. 268:19744–19752.PubMedGoogle Scholar
  144. Suzuki, T., Park, H., Hollingsworth, N.M., et al. (2000). PNG1, a yeast gene encoding a highly conserved peptide: N-glycanase. J. Cell Biol. 149:1039–1052.PubMedCrossRefGoogle Scholar
  145. Swanson, R., Locher, M., Hochstrasser, M. (2001). A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matalpha2 repressor degradation. Genes Dev. 15:2660–2674.PubMedCrossRefGoogle Scholar
  146. Szathmary, R., Bielmann, R., Nita-Lazar, M., et al. (2005). Yos9 protein is essential for degradation of misfolded glycoproteins and may function as lectin in ERAD. Mol. Cell 19:765–775.PubMedCrossRefGoogle Scholar
  147. Takeuchi, S. (2006). Molecular cloning, sequence, function and structural basis of human heart 150 kDa oxygen-regulated protein, an ER chaperone. Protein J. 25:517–528.PubMedCrossRefGoogle Scholar
  148. Taxis, C., Hitt, R., Park, S.H., et al. (2003). Use of modular substrates demonstrates mechanistic diversity and reveals differences in chaperone requirement of ERAD. J. Biol. Chem. 278:35903–35913.PubMedCrossRefGoogle Scholar
  149. Travers, K.J., Patil, C.K., Wodicka, L., et al. (2000). Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101:249–258.PubMedCrossRefGoogle Scholar
  150. Tsai, B., Ye, Y., Rapoport, T.A. (2002). Retro-translocation of proteins from the endoplasmic reticulum into the cytosol. Nat. Rev. Mol. Cell. Biol. 3:246–255.PubMedCrossRefGoogle Scholar
  151. Ushioda, R., Hoseki, J., Araki, K., et al. (2008). ERdj5 is required as a disulfide reductase for degradation of misfolded proteins in the ER. Science 321:569–572.PubMedCrossRefGoogle Scholar
  152. Vashist, S., and Ng, D.T. (2004). Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control. J. Cell Biol. 165:41–52.PubMedCrossRefGoogle Scholar
  153. Wahlman, J., DeMartino, G.N., Skach, W.R., et al. (2007). Real-time fluorescence detection of ERAD substrate retrotranslocation in a mammalian in vitro system. Cell 129:943–955.PubMedCrossRefGoogle Scholar
  154. Wakabayashi-Nakao, K., Tamura, A., Furukawa, T., et al. (2009). Quality control of human ABCG2 protein in the endoplasmic reticulum: ubiquitination and proteasomal degradation. Adv. Drug Deliv. Rev. 61:66–72.PubMedCrossRefGoogle Scholar
  155. Walter, J., Urban, J., Volkwein, C., et al. (2001). Sec61p-independent degradation of the tail-anchored ER membrane protein Ubc6p. EMBO J. 20:3124–3131.PubMedCrossRefGoogle Scholar
  156. Wang, G., Sawai, N., Kotliarova, S., et al. (2000). Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B. Hum. Mol. Genet. 9:1795–1803.PubMedCrossRefGoogle Scholar
  157. Wang, L., Dong, H., Soroka, C.J., et al. (2008). Degradation of the bile salt export pump at endoplasmic reticulum in progressive familial intrahepatic cholestasis type II. Hepatology 48:1558–1569.PubMedCrossRefGoogle Scholar
  158. Wang, Q., and Chang, A. (1999). Eps1, a novel PDI-related protein involved in ER quality control in yeast. EMBO J. 18:5972–5982.PubMedCrossRefGoogle Scholar
  159. Ward, C.L., Omura, S., Kopito, R.R. (1995). Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 83: 121–127.PubMedCrossRefGoogle Scholar
  160. Weihl, C.C., Dalal, S., Pestronk, A., et al. (2006). Inclusion body myopathy-associated mutations in p97/VCP impair endoplasmic reticulum-associated degradation. Hum. Mol. Genet. 15:189–199.PubMedCrossRefGoogle Scholar
  161. Werner, E.D., Brodsky, J.L., McCracken, A.A. (1996). Proteasome-dependent endoplasmic reticulum-associated protein degradation: an unconventional route to a familiar fate. Proc. Natl. Acad. Sci. USA. 93:13797–13801.PubMedCrossRefGoogle Scholar
  162. Wiertz, E.J., Tortorella, D., Bogyo, M., et al. (1996). Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384: 432–438.PubMedCrossRefGoogle Scholar
  163. Willer, M., Forte, G.M., Stirling, C.J. (2008). 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. 283:33883–33888.PubMedCrossRefGoogle Scholar
  164. Wright, R., Basson, M., D’Ari, L., et al. (1988). Increased amounts of HMG-CoA reductase induce “karmellae”: a proliferation of stacked membrane pairs surrounding the yeast nucleus. J. Cell Biol. 107:101–114.PubMedCrossRefGoogle Scholar
  165. Wu, J., and Kaufman, R.J. (2006). From acute ER stress to physiological roles of the Unfolded Protein Response. Cell Death Differ. 13:374–384.PubMedCrossRefGoogle Scholar
  166. Yagishita, N., Yamasaki, S., Nishioka, K., et al. (2008). Synoviolin, protein folding and the maintenance of joint homeostasis. Nat. Clin. Pract. Rheumatol. 4:91–97.PubMedCrossRefGoogle Scholar
  167. Ye, Y., Meyer, H.H., Rapoport, T.A. (2001). The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414:652–656.PubMedCrossRefGoogle Scholar
  168. Ye, Y., Shibata, Y., Yun, C., et al. (2004). A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429:841–847.PubMedCrossRefGoogle Scholar
  169. Younger, J.M., Chen. L., Ren, H.Y., et al. (2006). Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator. Cell 126:571–582.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Université Catholique de Louvain, Institut des Sciences de la Vie, Unité de Biochimie PhysiologiqueLouvain-la-NeuveBelgium

Personalised recommendations