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The ubiquitylation machinery of the endoplasmic reticulum

Abstract

As proteins travel through the endoplasmic reticulum (ER), a quality-control system retains newly synthesized polypeptides and supports their maturation. Only properly folded proteins are released to their designated destinations. Proteins that cannot mature are left to accumulate, impairing the function of the ER. To maintain homeostasis, the protein-quality-control system singles out aberrant polypeptides and delivers them to the cytosol, where they are destroyed by the proteasome. The importance of this pathway is evident from the growing list of pathologies associated with quality-control defects in the ER.

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Figure 1: Protein degradation at the endoplasmic reticulum (ER).
Figure 2: Mechanism of protein degradation in yeast and mammalian cells.
Figure 3: Protein homeostasis in the ER.
Figure 4: Processing of N-linked glycans in the yeast and mammalian ER.

References

  1. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    ADS  CAS  PubMed  Google Scholar 

  2. Schubert, U. et al. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404, 770–774 (2000).

    ADS  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  4. Gurkan, C., Stagg, S. M., Lapointe, P. & Balch, W. E. The COPII cage: unifying principles of vesicle coat assembly. Nature Rev. Mol. Cell Biol. 7, 727–738 (2006).

    Google Scholar 

  5. Wiseman, R. L., Powers, E. T., Buxbaum, J. N., Kelly, J. W. & Balch, W. E. An adaptable standard for protein export from the endoplasmic reticulum. Cell 131, 809–821 (2007).

    CAS  PubMed  Google Scholar 

  6. Daniels, R., Kurowski, B., Johnson, A. E. & Hebert, D. N. N-linked glycans direct the cotranslational folding pathway of influenza hemagglutinin. Mol. Cell 11, 79–90 (2003).

    CAS  PubMed  Google Scholar 

  7. Molinari, M. N-glycan structure dictates extension of protein folding or onset of disposal. Nature Chem. Biol. 3, 313–320 (2007).

    ADS  CAS  Google Scholar 

  8. Solda, T., Galli, C., Kaufman, R. J. & Molinari, M. Substrate-specific requirements for UGT1-dependent release from calnexin. Mol. Cell 27, 238–249 (2007). This study shows that some substrates are released from the calnexin cycle after one binding event, whereas others undergo several binding rounds.

    CAS  PubMed  Google Scholar 

  9. Hebert, D. N., Foellmer, B. & Helenius, A. Glucose trimming and reglucosylation determine glycoprotein association with calnexin in the endoplasmic reticulum. Cell 81, 425–433 (1995).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Camirand, A., Heysen, A., Grondin, B. & Herscovics, A. Glycoprotein biosynthesis in Saccharomyces cerevisiae. Isolation and characterization of the gene encoding a specific processing α-mannosidase. J. Biol. Chem. 266, 15120–15127 (1991).

    CAS  PubMed  Google Scholar 

  12. Jelinek-Kelly, S. & Herscovics, A. Glycoprotein biosynthesis in Saccharomyces cerevisiae. Purification of the α-mannosidase which removes one specific mannose residue from Man9GlcNAc. J. Biol. Chem. 263, 14757–14763 (1988).

    CAS  PubMed  Google Scholar 

  13. Jakob, C. A., Burda, P., Roth, J. & Aebi, M. Degradation of misfolded endoplasmic reticulum glycoproteins in Saccharomyces cerevisiae is determined by a specific oligosaccharide structure. J. Cell Biol. 142, 1223–1233 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Hosokawa, N. et al. A novel ER α-mannosidase-like protein accelerates ER-associated degradation. EMBO Rep. 2, 415–422 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Clerc, S. et al. Htm1 protein generates the N-glycan signal for glycoprotein degradation in the endoplasmic reticulum. J. Cell Biol. 184, 159–172 (2009). This study identified Htm1 as a factor involved in the generation of mannose 7 oligosaccharides on ERAD substrates.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Olivari, S. & Molinari, M. Glycoprotein folding and the role of EDEM1, EDEM2 and EDEM3 in degradation of folding-defective glycoproteins. FEBS Lett. 581, 3658–3664 (2007).

    CAS  PubMed  Google Scholar 

  18. Tremblay, L. O. & Herscovics, A. Cloning and expression of a specific human α1,2-mannosidase that trims Man9GlcNAc2 to Man8GlcNAc2 isomer B during N-glycan biosynthesis. Glycobiology 9, 1073–1078 (1999).

    CAS  PubMed  Google Scholar 

  19. Avezov, E., Frenkel, Z., Ehrlich, M., Herscovics, A. & Lederkremer, G. Z. Endoplasmic reticulum (ER) mannosidase I is compartmentalized and required for N-glycan trimming to Man5–6GlcNAc2 in glycoprotein ER-associated degradation. Mol. Biol. Cell 19, 216–225 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hosokawa, N. et al. Enhancement of endoplasmic reticulum (ER) degradation of misfolded Null Hong Kong α1-antitrypsin by human ER mannosidase I. J. Biol. Chem. 278, 26287–26294 (2003).

    CAS  PubMed  Google Scholar 

  21. Wu, Y., Swulius, M. T., Moremen, K. W. & Sifers, R. N. Elucidation of the molecular logic by which misfolded α1-antitrypsin is preferentially selected for degradation. Proc. Natl Acad. Sci. USA 100, 8229–8234 (2003).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hirao, K. et al. EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming. J. Biol. Chem. 281, 9650–9658 (2006).

    CAS  PubMed  Google Scholar 

  23. Olivari, S. et al. EDEM1 regulates ER-associated degradation by accelerating de-mannosylation of folding-defective polypeptides and by inhibiting their covalent aggregation. Biochem. Biophys. Res. Commun. 349, 1278–1284 (2006).

    CAS  PubMed  Google Scholar 

  24. Moremen, K. W. & Molinari, M. N-linked glycan recognition and processing: the molecular basis of endoplasmic reticulum quality control. Curr. Opin. Struct. Biol. 16, 592–599 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  27. Carvalho, P., Goder, V. & Rapoport, T. A. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126, 361–373 (2006).

    CAS  PubMed  Google Scholar 

  28. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    CAS  PubMed  Google Scholar 

  30. 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). References 29 and 30 characterize Hrd1 as an E3 ligase that ubiquitylates several ERAD substrates.

    CAS  PubMed  Google Scholar 

  31. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Buschhorn, B. A., Kostova, Z., Medicherla, B. & Wolf, D. H. A genome-wide screen identifies Yos9p as essential for ER-associated degradation of glycoproteins. FEBS Lett. 577, 422–426 (2004).

    CAS  PubMed  Google Scholar 

  33. Denic, V., Quan, E. M. & Weissman, J. S. A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell 126, 349–359 (2006).

    CAS  PubMed  Google Scholar 

  34. Gauss, R., Jarosch, E., Sommer, T. & Hirsch, C. A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery. Nature Cell Biol. 8, 849–854 (2006). References 33 and 34 show that Yos9 and Hrd3 act as a surveillance platform that binds to aberrant proteins and decodes the glycosylation status of a protein.

    CAS  PubMed  Google Scholar 

  35. Quan, E. M. et al. Defining the glycan destruction signal for endoplasmic reticulum-associated degradation. Mol. Cell 32, 870–877 (2008). This study characterizes N-glycans containing terminal α1,6-mannose as the preferred ligand of Yos9.

    CAS  PubMed  PubMed Central  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

  37. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kreft, S. G., Wang, L. & Hochstrasser, M. 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 (2006).

    CAS  PubMed  Google Scholar 

  39. 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).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  40. 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).

    CAS  PubMed  Google Scholar 

  41. Nadav, E. et al. A novel mammalian endoplasmic reticulum ubiquitin ligase homologous to the yeast Hrd1. Biochem. Biophys. Res. Commun. 303, 91–97 (2003).

    CAS  PubMed  Google Scholar 

  42. Mueller, B., Lilley, B. N. & Ploegh, H. L. SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER. J. Cell Biol. 175, 261–270 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kokame, K., Agarwala, K. L., Kato, H. & Miyata, T. Herp, a new ubiquitin-like membrane protein induced by endoplasmic reticulum stress. J. Biol. Chem. 275, 32846–32853 (2000).

    CAS  PubMed  Google Scholar 

  44. Schulze, A. et al. The ubiquitin-domain protein HERP forms a complex with components of the endoplasmic reticulum associated degradation pathway. J. Mol. Biol. 354, 1021–1027 (2005).

    CAS  PubMed  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

  46. 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). References 45 and 46 show that Derlin-1 is required for the membrane extraction of certain aberrant proteins from the ER.

    ADS  CAS  PubMed  Google Scholar 

  47. Bernasconi, R., Pertel, T., Luban, J. & Molinari, M. 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. 283, 16446–16454 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Christianson, J. C., Shaler, T. A., Tyler, R. E. & Kopito, R. R. OS-9 and GRP94 deliver mutant α1-antitrypsin to the Hrd1–SEL1L ubiquitin ligase complex for ERAD. Nature Cell Biol. 10, 272–282 (2008).

    CAS  PubMed  Google Scholar 

  49. Hosokawa, N. et al. Human XTP3-B forms an ER quality control scaffold with the HRD1–SEL1L ubiquitin ligase complex and BiP. J. Biol. Chem. 283, 20914–20924 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kaneko, M., Ishiguro, M., Niinuma, Y., Uesugi, M. & Nomura, Y. Human HRD1 protects against ER stress-induced apoptosis through ER-associated degradation. FEBS Lett. 532, 147–152 (2002).

    CAS  PubMed  Google Scholar 

  51. Cattaneo, M. et al. SEL1L and HRD1 are involved in the degradation of unassembled secretory Ig-µ chains. J. Cell. Physiol. 215, 794–802 (2008).

    CAS  PubMed  Google Scholar 

  52. Okuda-Shimizu, Y. & Hendershot, L. M. Characterization of an ERAD pathway for nonglycosylated BiP substrates, which require Herp. Mol. Cell 28, 544–554 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen, B. 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 103, 341–346 (2006).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shen, Y., Ballar, P. & Fang, S. Ubiquitin ligase gp78 increases solubility and facilitates degradation of the Z variant of α1-antitrypsin. Biochem. Biophys. Res. Commun. 349, 1285–1293 (2006).

    CAS  PubMed  Google Scholar 

  55. Song, B. L., Sever, N. & DeBose-Boyd, R. A. Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Mol. Cell 19, 829–840 (2005).

    CAS  PubMed  Google Scholar 

  56. Tsai, Y. C. et al. The ubiquitin ligase gp78 promotes sarcoma metastasis by targeting KAI1 for degradation. Nature Med. 13, 1504–1509 (2007).

    CAS  PubMed  Google Scholar 

  57. Hassink, G. et al. TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum. Biochem. J. 388, 647–655 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Younger, J. M. et al. Sequential quality-control checkpoints triage misfolded cystic fibrosis transmembrane conductance regulator. Cell 126, 571–582 (2006).

    CAS  PubMed  Google Scholar 

  59. McDonough, H. & Patterson, C. CHIP: a link between the chaperone and proteasome systems. Cell Stress Chaperones 8, 303–308 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang, B. et al. BAP31 interacts with Sec61 translocons and promotes retrotranslocation of CFTRΔF508 via the Derlin-1 complex. Cell 133, 1080–1092 (2008).

    CAS  PubMed  Google Scholar 

  61. Kitada, T. et al. Mutations in the Parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

    ADS  CAS  PubMed  Google Scholar 

  62. 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).

    CAS  PubMed  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

  64. 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).

    ADS  CAS  PubMed  Google Scholar 

  65. 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).

    ADS  CAS  PubMed  Google Scholar 

  66. Ploegh, H. L. A lipid-based model for the creation of an escape hatch from the endoplasmic reticulum. Nature 448, 435–438 (2007).

    ADS  CAS  PubMed  Google Scholar 

  67. Gauss, R., Sommer, T. & Jarosch, E. The Hrd1p ligase complex forms a linchpin between ER-lumenal substrate selection and Cdc48p recruitment. EMBO J. 25, 1827–1835 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Lilley, B. N. & Ploegh, H. L. Multiprotein complexes that link dislocation, ubiquitination, and extraction of misfolded proteins from the endoplasmic reticulum membrane. Proc. Natl Acad. Sci. USA 102, 14296–14301 (2005).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  71. Oda, Y. 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. 172, 383–393 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 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).

    CAS  PubMed  Google Scholar 

  73. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 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).

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  77. 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). References 74–77 demonstrate that yeast Cdc48, or p97 in mammals, mobilizes ERAD substrates from the ER membrane.

    ADS  CAS  PubMed  Google Scholar 

  78. Zhang, X. et al. Structure of the AAA ATPase p97. Mol. Cell 6, 1473–1484 (2000).

    CAS  PubMed  Google Scholar 

  79. DeLaBarre, B., Christianson, J. C., Kopito, R. R. & Brunger, A. T. Central pore residues mediate the p97/VCP activity required for ERAD. Mol. Cell 22, 451–462 (2006).

    CAS  PubMed  Google Scholar 

  80. Neuber, O., Jarosch, E., Volkwein, C., Walter, J. & Sommer, T. Ubx2 links the Cdc48 complex to ER-associated protein degradation. Nature Cell Biol. 7, 993–998 (2005).

    CAS  PubMed  Google Scholar 

  81. Schuberth, C. & Buchberger, A. Membrane-bound Ubx2 recruits Cdc48 to ubiquitin ligases and their substrates to ensure efficient ER-associated protein degradation. Nature Cell Biol. 7, 999–1006 (2005).

    CAS  PubMed  Google Scholar 

  82. Liang, J. et al. Characterization of erasin (UBXD2): a new ER protein that promotes ER-associated protein degradation. J. Cell Sci. 119, 4011–4024 (2006).

    CAS  PubMed  Google Scholar 

  83. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Richly, H. et al. A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting. Cell 120, 73–84 (2005). This study demonstrates how components of the ubiquitin–proteasome system cooperate to deliver ubiquitylated proteins to the proteasome.

    CAS  PubMed  Google Scholar 

  85. Deveraux, Q., Jensen, C. & Rechsteiner, M. Molecular cloning and expression of a 26S protease subunit enriched in dileucine repeats. J. Biol. Chem. 270, 23726–23729 (1995).

    CAS  PubMed  Google Scholar 

  86. Husnjak, K. et al. Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature 453, 481–488 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. Schreiner, P. et al. Ubiquitin docking at the proteasome through a novel pleckstrin-homology domain interaction. Nature 453, 548–552 (2008).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  89. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Misaghi, S., Pacold, M., Blom, D., Ploegh, H. L. & Korbel, G. A. Using a small molecule inhibitor of peptide:N-glycanase to probe its role in glycoprotein turnover. Chem. Biol. 11, 1677–1687 (2004).

    CAS  PubMed  Google Scholar 

  91. Hu, M. et al. Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14. EMBO J. 24, 3747–3756 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Verma, R. et al. Role of Rpn11 metalloprotease in deubiquitination and degradation by the 26S proteasome. Science 298, 611–615 (2002).

    ADS  CAS  PubMed  Google Scholar 

  93. Yao, T. & Cohen, R. E. A cryptic protease couples deubiquitination and degradation by the proteasome. Nature 419, 403–407 (2002).

    ADS  CAS  PubMed  Google Scholar 

  94. Ron, D. & Walter, P. Signal integration in the endoplasmic reticulum unfolded protein response. Nature Rev. Mol. Cell Biol. 8, 519–529 (2007).

    CAS  Google Scholar 

  95. Hollien, J. & Weissman, J. S. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313, 104–107 (2006).

    ADS  CAS  PubMed  Google Scholar 

  96. Kang, S. W. et al. Substrate-specific translocational attenuation during ER stress defines a pre-emptive quality control pathway. Cell 127, 999–1013 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Hammarstrom, P. et al. D18G transthyretin is monomeric, aggregation prone, and not detectable in plasma and cerebrospinal fluid: a prescription for central nervous system amyloidosis? Biochemistry 42, 6656–6663 (2003).

    PubMed  Google Scholar 

  98. Sekijima, Y. et al. Energetic characteristics of the new transthyretin variant A25T may explain its atypical central nervous system pathology. Lab. Invest. 83, 409–417 (2003).

    CAS  PubMed  Google Scholar 

  99. Sekijima, Y. et al. The biological and chemical basis for tissue-selective amyloid disease. Cell 121, 73–85 (2005).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all members of the Sommer laboratory for critical reading of the manuscript. We apologize to those authors whose work could not be cited because of space limitations. Work in T.S.'s laboratory is supported by the German Research Foundation (DFG) and the RUBICON Network of Excellence. R.G. was a fellow of the Boehringer Ingelheim Fonds. S.C.H. is the recipient of a Helmholtz PhD fellowship.

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Hirsch, C., Gauss, R., Horn, S. et al. The ubiquitylation machinery of the endoplasmic reticulum. Nature 458, 453–460 (2009). https://doi.org/10.1038/nature07962

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