Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

ERAD: the long road to destruction

Abstract

Endoplasmic reticulum (ER)-associated protein degradation (ERAD) eliminates misfolded or unassembled proteins from the ER. ERAD targets are selected by a quality control system within the ER lumen and are ultimately destroyed by the cytoplasmic ubiquitin–proteasome system (UPS). The spatial separation between substrate selection and degradation in ERAD requires substrate transport from the ER to the cytoplasm by a process termed dislocation. In this review, we will summarize advances in various aspects of ERAD and discuss new findings on how substrate dislocation is achieved.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The ubiquitin–proteasome system (UPS).
Figure 2: Proteasomal degradation of ERAD targets.
Figure 3: Mechanisms for initiating dislocation.

Similar content being viewed by others

References

  1. Matlack, K. E., Mothes, W. & Rapoport, T. A. Protein translocation: tunnel vision. Cell 92, 381–390 (1998).

    Article  CAS  PubMed  Google Scholar 

  2. Bonifacino, J. S., Suzuki, C. K., Lippincott-Schwartz, J., Weissman, A. M. & Klausner, R. D. Pre-Golgi degradation of newly synthesized T-cell antigen receptor chains: intrinsic sensitivity and the role of subunit assembly. J. Cell Biol. 109, 73–83 (1989).

    Article  CAS  PubMed  Google Scholar 

  3. Cheng, S. H. et al. Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell 63, 827–834 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Jensen, T. J. et al. Multiple proteolytic systems, including the proteasome, contribute to CFTR processing. Cell 83, 129–135 (1995).

    Article  CAS  PubMed  Google Scholar 

  5. Ward, C. L., Omura, S. & Kopito, R. R. Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 83, 121–127 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Sommer, T. & Jentsch, S. A protein translocation defect linked to ubiquitin conjugation at the endoplasmic reticulum. Nature 365, 176–179 (1993).

    Article  CAS  PubMed  Google Scholar 

  7. Biederer, T., Volkwein, C. & Sommer, T. Degradation of subunits of the Sec61p complex, an integral component of the ER membrane, by the ubiquitin-proteasome pathway. EMBO J. 15, 2069–2076 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hiller, M. M., Finger, A., Schweiger, M. & Wolf, D. H. ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science 273, 1725–1728 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Biederer, T., Volkwein, C. & Sommer, T. Role of Cue1p in ubiquitination and degradation at the ER surface. Science 278, 1806–1809 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Wiertz, E. J. et al. Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384, 432–438 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Hampton, R. Y. Proteolysis and sterol regulation. Annu. Rev. Cell Dev. Biol. 18, 345–378 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Hampton, R. Y., Gardner, R. G. & 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 7, 2029–2044 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bays, N. W., Gardner, R. G., Seelig, L. P., Joazeiro, C. A. & Hampton, R. Y. Hrd1p/Der3p is a membrane-anchored ubiquitin ligase required for ER-associated degradation. Nature Cell Biol. 3, 24–29 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Deak, P. M. & Wolf, D. H. Membrane topology and function of Der3/Hrd1p as a ubiquitin-protein ligase (E3) involved in endoplasmic reticulum degradation. J. Biol. Chem. 276, 10663–10669 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Bordallo, J., Plemper, R. K., Finger, A. & Wolf, D. H. Der3p/Hrd1p is required for endoplasmic reticulum-associated degradation of misfolded lumenal and integral membrane proteins. Mol. Biol. Cell 9, 209–222 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Friedlander, R., Jarosch, E., Urban, J., Volkwein, C. & Sommer, T. A regulatory link between ER-associated protein degradation and the unfolded-protein response. Nature Cell Biol. 2, 379–384 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Gardner, R. G. et al. Endoplasmic reticulum degradation requires lumen to cytosol signaling. Transmembrane control of Hrd1p by Hrd3p. J. Cell Biol. 151, 69–82 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shearer, A. G. & Hampton, R. Y. Structural control of endoplasmic reticulum-associated degradation: effect of chemical chaperones on 3-hydroxy-3-methylglutaryl-CoA reductase. J. Biol. Chem. 279, 188–196 (2004).

    Article  CAS  PubMed  Google Scholar 

  19. Shearer, A. G. & Hampton, R. Y. Lipid-mediated, reversible misfolding of a sterol-sensing domain protein. EMBO J. 24, 149–159 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Swanson, R., Locher, M. & Hochstrasser, M. A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matα2 repressor degradation. Genes Dev. 15, 2660–2674 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Vashist, S. & Ng, D. T. Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control. J. Cell Biol. 165, 41–52 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kikkert, M. et al. Human HRD1 is an E3 ubiquitin ligase involved in degradation of proteins from the endoplasmic reticulum. J. Biol. Chem. 279, 3525–3534 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Lenk, U. et al. A role for mammalian Ubc6 homologues in ER-associated protein degradation. J. Cell Sci. 115, 3007–3014 (2002).

    CAS  PubMed  Google Scholar 

  24. Fang, S. 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 98, 14422–14427 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Meacham, G. C., Patterson, C., Zhang, W., Younger, J. M. & Cyr, D. M. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nature Cell Biol. 3, 100–105 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Connell, P. et al. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nature Cell Biol. 3, 93–96 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Imai, Y. et al. CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Mol. Cell 10, 55–67 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Imai, Y. et al. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105, 891–902 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Yoshida, Y. et al. E3 ubiquitin ligase that recognizes sugar chains. Nature 418, 438–442 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Yoshida, Y. et al. Fbs2 is a new member of the E3 ubiquitin ligase family that recognizes sugar chains. J. Biol. Chem. 278, 43877–43884 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Hirsch, C., Blom, D. & Ploegh, H. L. A role for N-glycanase in the cytosolic turnover of glycoproteins. EMBO J. 22, 1036–1046 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Suzuki, T., Park, H., Hollingsworth, N. M., Sternglanz, R. & Lennarz, W. J. PNG1, a yeast gene encoding a highly conserved peptide:N-glycanase. J. Cell Biol. 149, 1039–1052 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tanaka, K., Suzuki, T., Hattori, N. & Mizuno, Y. Ubiquitin, proteasome and parkin. Biochim. Biophys. Acta 1695, 235–247 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Gelman, M. S. & Kopito, R. R. Rescuing protein conformation: prospects for pharmacological therapy in cystic fibrosis. J. Clin. Invest. 110, 1591–1597 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chauhan, D., Hideshima, T., Mitsiades, C., Richardson, P. & Anderson, K. C. Proteasome inhibitor therapy in multiple myeloma. Mol. Cancer Ther. 4, 686–692 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Johnston, J. A., Ward, C. L. & Kopito, R. R. Aggresomes: a cellular response to misfolded proteins. J. Cell Biol. 143, 1883–1898 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Younger, J. M. et al. A foldable CFTRΔF508 biogenic intermediate accumulates upon inhibition of the Hsc70-CHIP E3 ubiquitin ligase. J. Cell Biol. 167, 1075–1085 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Helenius, A. & Aebi, M. Roles of N-linked glycans in the endoplasmic reticulum. Annu. Rev. Biochem. 73, 1019–1049 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Trombetta, E. S. & Parodi, A. J. Quality control and protein folding in the secretory pathway. Annu. Rev. Cell Dev. Biol. 19, 649–676 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Jakob, C. A. et al. Htm1p, a mannosidase-like protein, is involved in glycoprotein degradation in yeast. EMBO Rep. 2, 423–430 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Molinari, M., Calanca, V., Galli, C., Lucca, P. & Paganetti, P. Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle. Science 299, 1397–1400 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Oda, Y., Hosokawa, N., Wada, I. & Nagata, K. EDEM as an acceptor of terminally misfolded glycoproteins released from calnexin. Science 299, 1394–1397 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Olivari, S., Galli, C., Alanen, H., Ruddock, L. & Molinari, M. A novel stress-induced EDEM variant regulating endoplasmic reticulum-associated glycoprotein degradation. J. Biol. Chem. 280, 2424–2428 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Plemper, R. K., Bohmler, S., Bordallo, J., Sommer, T. & Wolf, D. H. Mutant analysis links the translocon and BiP to retrograde protein transport for ER degradation. Nature 388, 891–895 (1997).

    Article  CAS  PubMed  Google Scholar 

  45. Anelli, T. et al. Thiol-mediated protein retention in the endoplasmic reticulum: the role of ERp44. EMBO J. 22, 5015–5022 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tsai, B., Rodighiero, C., Lencer, W. I. & Rapoport, T. A. Protein disulfide isomerase acts as a redox-dependent chaperone to unfold cholera toxin. Cell 104, 937–948 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Wang, Q. & Chang, A. Substrate recognition in ER-associated degradation mediated by Eps1, a member of the protein disulfide isomerase family. EMBO J. 22, 3792–3802 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gewurz, B. E. et al. Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2. Proc. Natl Acad. Sci. USA 98, 6794–6799 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Joliot, A. & Prochiantz, A. Transduction peptides: from technology to physiology. Nature Cell Biol. 6, 189–196 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Pariyarath, R. et al. Co-translational interactions of apoprotein B with the ribosome and translocon during lipoprotein assembly or targeting to the proteasome. J. Biol. Chem. 276, 541–550 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Pilon, M., Schekman, R. & Romisch, K. Sec61p mediates export of a misfolded secretory protein from the endoplasmic reticulum to the cytosol for degradation. EMBO J. 16, 4540–4548 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tirosh, B., Furman, M. H., Tortorella, D. & Ploegh, H. L. Protein unfolding is not a prerequisite for endoplasmic reticulum-to-cytosol dislocation. J. Biol. Chem. 278, 6664–6672 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Fiebiger, E., Story, C., Ploegh, H. L. & Tortorella, D. Visualization of the ER-to-cytosol dislocation reaction of a type I membrane protein. EMBO J. 21, 1041–1053 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Blom, D., Hirsch, C., Stern, P., Tortorella, D. & Ploegh, H. L. A glycosylated type I membrane protein becomes cytosolic when peptide: N-glycanase is compromised. EMBO J. 23, 650–658 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Van den Berg, B. et al. X-ray structure of a protein-conducting channel. Nature 427, 36–44 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Clemons, W. M. Jr, Menetret, J. F., Akey, C. W. & Rapoport, T. A. Structural insight into the protein translocation channel. Curr. Opin. Struct. Biol. 14, 390–396 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Hamman, B. D., Chen, J. C., Johnson, E. E. & Johnson, A. E. The aqueous pore through the translocon has a diameter of 40–60 Å during cotranslational protein translocation at the ER membrane. Cell 89, 535–544 (1997).

    Article  CAS  PubMed  Google Scholar 

  58. Wirth, A. et al. The Sec61p complex is a dynamic precursor activated channel. Mol. Cell 12, 261–268 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Schnell, D. J. & Hebert, D. N. Protein translocons: multifunctional mediators of protein translocation across membranes. Cell 112, 491–505 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Knop, M., Finger, A., Braun, T., Hellmuth, K. & Wolf, D. H. Der1, a novel protein specifically required for endoplasmic reticulum degradation in yeast. EMBO J. 15, 753–763 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ye, Y., Shibata, Y., Yun, C., Ron, D. & Rapoport, T. A. A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429, 841–847 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Lilley, B. N. & Ploegh, H. L. A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429, 834–840 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Hitt, R. & Wolf, D. H. 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 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. Taxis, C. et al. Use of modular substrates demonstrates mechanistic diversity and reveals differences in chaperone requirement of ERAD. J. Biol. Chem. 278, 35903–35913 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. de Virgilio, M., Weninger, H. & Ivessa, N. E. Ubiquitination is required for the retro-translocation of a short-lived luminal endoplasmic reticulum glycoprotein to the cytosol for degradation by the proteasome. J. Biol. Chem. 273, 9734–9743 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Shamu, C. E., Flierman, D., Ploegh, H. L., Rapoport, T. A. & Chau, V. Polyubiquitination is required for US11-dependent movement of MHC class I heavy chain from endoplasmic reticulum into cytosol. Mol. Biol. Cell 12, 2546–2555 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mayer, T. U., Braun, T. & Jentsch, S. Role of the proteasome in membrane extraction of a short-lived ER-transmembrane protein. EMBO J. 17, 3251–3257 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Walter, J., Urban, J., Volkwein, C. & Sommer, T. Sec61p-independent degradation of the tail-anchored ER membrane protein Ubc6p. EMBO J. 20, 3124–3131 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Hirsch, C. & Ploegh, H. L. Intracellular targeting of the proteasome. Trends Cell Biol. 10, 268–272 (2000).

    Article  CAS  PubMed  Google Scholar 

  70. Lee, R. J. et al. Uncoupling retro-translocation and degradation in the ER-associated degradation of a soluble protein. EMBO J. 23, 2206–2215 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Jarosch, E. et al. Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nature Cell Biol. 4, 134–139 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Bays, N. W., Wilhovsky, S. K., Goradia, A., Hodgkiss-Harlow, K. & Hampton, R. Y. HRD4/NPL4 is required for the proteasomal processing of ubiquitinated ER proteins. Mol. Biol. Cell 12, 4114–4128 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Ye, Y., Meyer, H. H. & Rapoport, T. A. The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414, 652–656 (2001).

    Article  CAS  PubMed  Google Scholar 

  74. Rabinovich, E., Kerem, A., Frohlich, K. U., Diamant, N. & Bar-Nun, S. AAA-ATPase p97/Cdc48p, a cytosolic chaperone required for endoplasmic reticulum-associated protein degradation. Mol. Cell. Biol. 22, 626–634 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Braun, S., Matuschewski, K., Rape, M., Thoms, S. & Jentsch, S. Role of the ubiquitin-selective CDC48(UFD1/NPL4) chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J. 21, 615–621 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Meyer, H. H., Wang, Y. & Warren, G. Direct binding of ubiquitin conjugates by the mammalian p97 adaptor complexes, p47 and Ufd1-Npl4. EMBO J. 21, 5645–5652 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ye, Y., Meyer, H. H. & Rapoport, T. A. Function of the p97-Ufd1-Npl4 complex in retrotranslocation from the ER to the cytosol: dual recognition of nonubiquitinated polypeptide segments and polyubiquitin chains. J. Cell Biol. 162, 71–84 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Neupert, W. & Brunner, M. The protein import motor of mitochondria. Nature Rev. Mol. Cell Biol. 3, 555–565 (2002).

    Article  CAS  Google Scholar 

  79. Zhong, X. et al. AAA ATPase p97/valosin-containing protein interacts with gp78, a ubiquitin ligase for endoplasmic reticulum-associated degradation. J. Biol. Chem. 279, 45676–45684 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Rape, M. et al. Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone. Cell 107, 667–677 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Hitchcock, A. L. et al. The conserved npl4 protein complex mediates proteasome-dependent membrane-bound transcription factor activation. Mol. Biol. Cell 12, 3226–3241 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schuberth, C., Richly, H., Rumpf, S. & Buchberger, A. Shp1 and Ubx2 are adaptors of Cdc48 involved in ubiquitin-dependent protein degradation. EMBO Rep. 5, 818–824 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Richly, H. et al. A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 120, 73–84 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Elsasser, S., Chandler-Militello, D., Muller, B., Hanna, J. & Finley, D. Rad23 and Rpn10 serve as alternative ubiquitin receptors for the proteasome. J. Biol. Chem. 279, 26817–26822 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Medicherla, B., Kostova, Z., Schaefer, A. & Wolf, D. H. A genomic screen identifies Dsk2p and Rad23p as essential components of ER-associated degradation. EMBO Rep. 5, 692–697 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Suzuki, T., Park, H., Kwofie, M. A. & Lennarz, W. J. Rad23 provides a link between the Png1 deglycosylating enzyme and the 26 S proteasome in yeast. J. Biol. Chem. 276, 21601–21607 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Yu, H. & Kopito, R. R. The role of multiubiquitination in dislocation and degradation of the α subunit of the T cell antigen receptor. J. Biol. Chem. 274, 36852–36858 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Shamu, C. E., Story, C. M., Rapoport, T. A. & Ploegh, H. L. The pathway of US11-dependent degradation of MHC class I heavy chains involves a ubiquitin-conjugated intermediate. J. Cell Biol. 147, 45–58 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Furman, M. H., Loureiro, J., Ploegh, H. L. & Tortorella, D. Ubiquitinylation of the cytosolic domain of a type I membrane protein is not required to initiate its dislocation from the endoplasmic reticulum. J. Biol. Chem. 278, 34804–34811 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Bour, S., Schubert, U. & Strebel, K. The human immunodeficiency virus type 1 Vpu protein specifically binds to the cytoplasmic domain of CD4: implications for the mechanism of degradation. J. Virol. 69, 1510–1520 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Schubert, U. et al. CD4 glycoprotein degradation induced by human immunodeficiency virus type 1 Vpu protein requires the function of proteasomes and the ubiquitin-conjugating pathway. J. Virol. 72, 2280–2288 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Willey, R. L., Maldarelli, F., Martin, M. A. & Strebel, K. Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4. J. Virol. 66, 7193–7200 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Schubert, U. et al. Human-immunodeficiency-virus-type-1-encoded Vpu protein is phosphorylated by casein kinase II. Eur. J. Biochem. 204, 875–883 (1992).

    Article  CAS  PubMed  Google Scholar 

  94. Laney, J. D. & Hochstrasser, M. Substrate targeting in the ubiquitin system. Cell 97, 427–430 (1999).

    Article  CAS  PubMed  Google Scholar 

  95. Margottin, F. et al. A novel human WD protein, h-β TrCp, that interacts with HIV-1 Vpu connects CD4 to the ER degradation pathway through an F-box motif. Mol. Cell 1, 565–574 (1998).

    Article  CAS  PubMed  Google Scholar 

  96. Meusser, B. & Sommer, T. Vpu-mediated degradation of CD4 reconstituted in yeast reveals mechanistic differences to cellular ER-associated protein degradation. Mol. Cell 14, 247–258 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Schubert, U. & Strebel, K. Differential activities of the human immunodeficiency virus type I-encoded Vpu protein are regulated by phosphorylation and occur in different cellular compartments. J. Virol. 68, 2260–2271 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Chen, M. Y., Maldarelli, F., Karezewski, M. K., Willey, R. L. & Strebel, K. Human immunodeficiency virus type I Vpu protein induces degradation of CD4 in vitro: the cytoplasmic domain of CD4 contributes to Vpu sensitivity. J. Virol. 67, 3877–3884 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We appreciate the helpful comments of the Sommer group on the manuscript. This work was partially supported by grants from the 'Deutsche Forschungs Gemeinschaft' to T.S. C.H. is a recipient of a Helmholtz Fellowship.

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meusser, B., Hirsch, C., Jarosch, E. et al. ERAD: the long road to destruction. Nat Cell Biol 7, 766–772 (2005). https://doi.org/10.1038/ncb0805-766

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb0805-766

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing