Key Points
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When newly synthesized proteins translocate into the endoplasmic reticulum (ER) lumen, they undergo 'quality control'. An elaborate system of chaperones helps proteins to fold and prevents misfolded polypeptides from reaching their final destination.
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; Misfolded proteins that cannot be brought back to their native state are degraded. Recent evidence indicates that misfolded proteins are retro-translocated from the ER lumen to the cytosol and are then degraded by the ubiquitin–proteasome system.
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The retro-translocation pathway is co-opted by certain viruses to degrade proteins that are involved in the immunoprotection of the host. It is also used by some plant and bacterial toxins to enter the cytosol of cells.
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; The first step in retro-translocation is the recognition of a misfolded substrate. Exposure of hydrophobic polypeptide patches might represent the general recognition signal and ER chaperones might be the signal receptors. An important player seems to be protein disulphide isomerase and its relatives. BiP and other chaperones have also been implicated in targeting misfolded substrates for retro-translocation.
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The next step in retro-translocation is the transport of the polypeptide chain across the ER membrane. On the basis of biochemical and genetic data, transport of the polypeptide seems to occur through the protein-conducting channel that is formed by the Sec61 complex. Given the size limitation of the Sec61 channel, it is likely that substrates need to be at least partially unfolded before they can pass through the channel.
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Polypeptide substrates that emerge from the translocation channel are polyubiquitylated at the membrane. The ubiquitylation machinery comprises both specific conjugation and ligase enzymes. However, polyubiquitylation alone is insufficient to release a substrate into the cytosol.
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Recent experiments indicate a role for a member of the AAA family of ATPases — Cdc48 in yeast and p97 in mammals — in extracting polypeptides from the ER membrane. These ATPases might 'pull' polypeptides out of the membrane in a similar manner to AAA proteases, which remove misfolded membrane proteins in bacteria and mitochondria.
Abstract
Proteins that are misfolded in the endoplasmic reticulum are transported back into the cytosol for destruction by the proteasome. This retro-translocation pathway has been co-opted by certain viruses, and by plant and bacterial toxins. The mechanism of retro-translocation is still mysterious, but several aspects of this process are now being unravelled.
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References
Matlack, K. E. S., Mothes, W. & Rapoport, T. A. Protein translocation — tunnel vision. Cell 92, 381–390 (1998).
Mori, K. Tripartite management of unfolded proteins in the endoplasmic reticulum. Cell 101, 451–454 (2000).
Travers, K. J. et al. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101, 249–258 (2000).
Casagrande, R. et al. Degradation of proteins from the ER of S. cerevisiae requires an intact unfolded protein response pathway. Mol. Cell 5, 729–735 (2000).
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).
Hong, E., Davidson, A. R. & Kaiser, C. A. A pathway for targeting soluble misfolded proteins to the yeast vacuole. J. Cell Biol. 135, 623–633 (1996).
Chang, A. & Fink, G. R. Targeting of the yeast plasma membrane [H+]ATPase: a novel gene AST1 prevents mislocalization of mutant ATPase to the vacuole. J. Cell Biol. 128, 39–49 (1995).
Klausner, R. D. & Sitia, R. Protein degradation in the endoplasmic reticulum. Cell 62, 611–614 (1990).
Kopito, R. R. ER quality control: the cytoplasmic connection. Cell 88, 427–430 (1997).
McCracken, A. A. & Brodsky, J. L. Assembly of ER-associated protein degradation in vitro: dependence on cytosol, calnexin, and ATP. J. Cell Biol. 132, 291–298 (1996).This report and reference 74 describe in vitro systems for the degradation of ER-associated proteins. Reference 10 first showed a cytosolic requirement for the degradation of a soluble ER protein.
Brodsky, J. L. & McCracken, A. A. ER protein quality control and proteasome-mediated protein degradation. Semin. Cell Dev. Biol. 10, 507–513 (1999).This review gives a list of ER-associated degradation substrates in yeast. Components that are required and not required for their degradation are listed. The table indicates that different degradation pathways exist.
Russell, W. An address on a characteristic organism of cancer. BMJ 2, 1356–1360 (1890).
Kopito, R. R. & Sitia, R. Aggresomes and Russell bodies. Symptoms of cellular indigestion? EMBO Rep. 1, 225–231 (2000).
Rivera, V. M. et al. Regulation of protein secretion through controlled aggregation in the endoplasmic reticulum. Science 287, 826–830 (2000).
Braakman, I., Helenius, J. & Helenius, A. Role of ATP and disulphide bonds during protein folding in the endoplasmic reticulum. Nature 356, 260–262 (1992).
Vashist, S. et al. Distinct retrieval and retention mechanisms are required for the quality control of endoplasmic reticulum protein folding. J. Cell Biol. 155, 355–368 (2001).This paper and reference 17 show that soluble, misfolded ER proteins must first be transported from the ER to the Golgi before they can be degraded.
Caldwell, S. R., Hill, K. J. & Cooper, A. A. Degradation of endoplasmic reticulum (ER) quality control substrates requires transport between the ER and Golgi. J. Biol. Chem. 276, 23296–23303 (2001).
Kamhi-Nesher, S. et al. A novel quality control compartment derived from the endoplasmic reticulum. Mol. Biol. Cell 12, 1711–1723 (2001).
Wiertz, E. J. H. J. et al. The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84, 769–779 (1996).
Wiertz, E. J. H. J. et al. Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384, 432–438 (1996).This paper provides the first evidence that the Sec61 channel might be involved in retro-translocation of ER proteins. It also shows that viruses can co-opt the cellular pathway.
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).
Boname, J. M. & Stevenson, P. G. MHC class I ubiquitination by a viral phd/lap finger protein. Immunity 15, 627–636 (2001).
Sandvig, K. & van Deurs, B. Entry of ricin and Shiga toxin into cells: molecular mechanisms and medical perspectives. EMBO J. 19, 5943–5950 (2000).
Lord, J. M. & Roberts, L. M. Toxin entry: retrograde transport through the secretory pathway. J. Cell Biol. 140, 733–736 (1998).
Lencer, W. I., Hirst, T. R. & Holmes, R. K. Membrane traffic and the cellular uptake of cholera toxin. Biochim. Biophys. Acta 1450, 177–190 (1999).
Schmitz, A., Herrgen, H., Winkeler, A. & Herzog, V. Cholera toxin is exported from microsomes by the Sec61p complex. J. Cell Biol. 148, 1203–1212 (2000).
Ellgaard, L. & Helenius, A. ER quality control: towards an understanding at the molecular level. Curr. Opin. Cell Biol. 13, 431–437 (2001).This review summarizes the current knowledge of quality control in the ER, with emphasis on the ER retention and degradation of glycoproteins.
Knop, M., Hauser, N. & Wolf, D. H. N-Glycosylation affects endoplasmic reticulum degradation of a mutated derivative of carboxypeptidase yscY in yeast. Yeast 12, 1229–1238 (1996).
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).This paper and reference 30 indicate that the generation of a Man8-containing carbohydrate chain targets a misfolded glycoprotein to the degradation machinery.
Liu, Y., Choudhury, P., Cabral, C. M. & Sifers, R. N. Oligosaccharide modification in the early secretory pathway directs the selection of a misfolded glycoprotein for degradation by the proteasome. J. Biol. Chem. 274, 5861–5867 (1999).
Hosokawa, N. et al. A novel ER α-mannosidase-like protein accelerates ER-associated degradation. EMBO Rep. 2, 415–422 (2001).
Nakatsukasa, K., Nishikawa, S., Hosokawa, N., Nagata, K. & Endo, T. Mnl1p, an α-mannosidase-like protein in yeast Saccharomyces cerevisiae, is required for endoplasmic reticulum-associated degradation of glycoproteins. J. Biol. Chem. 276, 8635–8638 (2001).
Jakob, C. A. et al. Htm1p, a mannosidase-like protein, is involved in glycoprotein degradation in yeast. EMBO Rep. 2, 423–430 (2001).
Tokunaga, F., Brostrom, C., Koide, T. & Arvan, P. Endoplasmic reticulum (ER)-associated degradation of misfolded N-linked glycoproteins is suppressed upon inhibition of ER mannosidase I. J. Biol. Chem. 275, 40757–40764 (2000).
Wilson, C. M., Farmery, M. R. & Bulleid, N. J. Pivotal role of calnexin and mannose trimming in regulating the endoplasmic reticulum-associated degradation of major histocompatibility complex class I heavy chain. J. Biol. Chem. 275, 21224–21232 (2000).
Gillece, P., Luz, J. M., Lennarz, W. J., de La Cruz, F. J. & Romisch, K. Export of a cysteine-free misfolded secretory protein from the endoplasmic reticulum for degradation requires interaction with protein disulfide isomerase. J. Cell. Biol. 147, 1443–1456 (1999).This paper, and references 40 and 41 , raise the possibility that PDI and related proteins could serve to unfold proteins in the ER lumen and to target substrates to the retro-translocation machinery.
Fagioli, C., Mezghrani, A. & Sitia, R. Reduction of interchain disulfide bonds precedes the dislocation of Ig-μ chains from the endoplasmic reticulum to the cytosol for proteasomal degradation. J. Biol. Chem. 276, 40962–40967 (2001).
Orlandi, P. A. Protein-disulfide isomerase-mediated reduction of the A subunit of cholera toxin in a human intestinal cell line. J. Biol. Chem. 272, 4591–4599 (1997).
Tortorella, D. et al. Dislocation of type I membrane proteins from the ER to the cytosol is sensitive to changes in redox potential. J. Cell Biol. 142, 365–376 (1998).
Wang, Q. & Chang, A. Eps1, a novel PDI-related protein involved in ER quality control in yeast. EMBO J. 18, 5972–5982 (1999).
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).
Knittler, M. R., Dirks, S. & Haas, I. G. Molecular chaperones involved in protein degradation in the endoplasmic reticulum: quantitative interaction of the heat shock cognate protein BiP with partially folded immunoglobulin light chains that are degraded in the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 92, 1764–1768 (1995).
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).
Brodsky, J. L. et al. The requirement for molecular chaperones during endoplasmic reticulum-associated protein degradation demonstrates that protein export and import are mechanistically distinct. J. Biol. Chem. 274, 3453–3460 (1999).
Matlack, K. E., Misselwitz, B., Plath, K. & Rapoport, T. A. BiP acts as a molecular ratchet during posttranslational transport of prepro-α-factor across the ER membrane. Cell 97, 553–564 (1999).
Chillaron, J. & Haas, I. G. Dissociation from BiP and retrotranslocation of unassembled immunoglobulin light chains are tightly coupled to proteasome activity. Mol. Biol. Cell 11, 217–226 (2000).
Misselwitz, B., Staeck, O. & Rapoport, T. A. J proteins catalytically activate Hsp70 molecules to trap a wide range of peptide sequences. Mol. Cell 2, 593–603 (1998).
Gillece, P., Pilon, M. & Romisch, K. The protein translocation channel mediates glycopeptide export across the endoplasmic reticulum membrane. Proc. Natl Acad. Sci. USA 97, 4609–4614 (2000).
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).
Nishikawa, S. I., Fewell, S. W., Kato, Y., Brodsky, J. L. & Endo, T. Molecular chaperones in the yeast endoplasmic reticulum maintain the solubility of proteins for retrotranslocation and degradation. J. Cell Biol. 153, 1061–1070 (2001).
Chen, Y., Le Caherec, F. & Chuck, S. L. Calnexin and other factors that alter translocation affect the rapid binding of ubiquitin to apoB in the Sec61 complex. J. Biol. Chem. 273, 11887–11894 (1998).
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).
Bebok, Z., Mazzochi, C., King, S. A., Hong, J. S. & Sorscher, E. J. The mechanism underlying cystic fibrosis transmembrane conductance regulator transport from the endoplasmic reticulum to the proteasome includes Sec61beta and a cytosolic, deglycosylated intermediary. J. Biol. Chem. 273, 29873–29878 (1998).
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).
Petaja-Repo, U. E. et al. Newly synthesized human δ-opioid receptors retained in the endoplasmic reticulum are retrotranslocated to the cytosol, deglycosylated, ubiquitinated, and degraded by the proteasome. J. Biol. Chem. 276, 4416–4423 (2001).
Wesche, J., Rapak, A. & Olsnes, S. Dependence of ricin toxicity on translocation of the toxin A-chain from the endoplasmic reticulum to the cytosol. J. Biol. Chem. 274, 34443–34449 (1999).
Simpson, J. C. et al. Ricin A chain utilises the endoplasmic reticulum-associated protein degradation pathway to enter the cytosol of yeast. FEBS Lett. 459, 80–84 (1999).
Zhou, M. & Schekman, R. The engagement of Sec61p in the ER dislocation process. Mol. Cell 4, 925–934 (1999).
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).
Kihara, A., Akiyama, Y. & Ito, K. Dislocation of membrane proteins in FtsH-mediated proteolysis. EMBO J. 18, 2970–2981 (1999).This paper and reference 61 show that misfolded proteins are extracted from bacterial and mitochondrial membranes by AAA proteases.
Leonhard, K. et al. Membrane protein degradation by AAA proteases in mitochondria: extraction of substrates from either membrane surface. Mol. Cell 5, 629–638 (2000).
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).
Menetret, J. et al. The structure of ribosome-channel complexes engaged in protein translocation. Mol. Cell 6, 1219–1232 (2000).
Beckmann, R. et al. Architecture of the protein-conducting channel associated with the translating 80S ribosome. Cell 107, 361–372 (2001).
Mitchell, D. M. et al. Apoprotein B100 has a prolonged interaction with the translocon during which its lipidation and translocation change from dependence on the microsomal triglyceride transfer protein to independence. Proc. Natl Acad. Sci. USA 95, 14733–14738 (1998).
Plemper, R. K., Deak, P. M., Otto, R. T. & Wolf, D. H. Re-entering the translocon from the lumenal side of the endoplasmic reticulum. Studies on mutated carboxypeptidase yscY species. FEBS Lett. 443, 241–245 (1999).
Heinrich, S. U., Mothes, W., Brunner, J. & Rapoport, T. A. The Sec61p complex mediates the integration of a membrane protein by allowing lipid partitioning of the transmembrane domain. Cell 102, 233–244 (2000).
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).
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).
Ward, C. L., Omura, S. & Kopito, R. R. Degradation of CFTR by the ubiquitin–proteasome pathway. Cell 83, 121–127 (1995).
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).
Kikkert, M. et al. Ubiquitination is essential for human cytomegalovirus US11-mediated dislocation of MHC class I molecules from the endoplasmic reticulum to the cytosol. Biochem. J. 358, 369–377 (2001).
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).
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).
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).This paper, and references 91, 97– 99 , show that the AAA ATPase Cdc48/p97 and its partners Ufd1 and Npl4 are involved in ER-protein degradation. The complex seems to extract proteins from the ER membrane.
Biederer, T., Volkwein, C. & Sommer, T. Role of Cue1p in ubiquitination and degradation at the ER surface. Science 278, 1806–1809 (1997).
Sommer, T. & Jentsch, S. A protein translocation defect linked to ubiquitin conjugation at the endoplasmic reticulum. Nature 365, 176–179 (1993).This paper gives the first evidence for the involvement of ubiquitylation in ER-protein degradation. The absence of a ubiquitin-conjugating enzyme (Ubc6) suppresses a sec61 mutant, which indicates that a misfolded membrane protein is stabilized.
Hampton, R. Y. & Bhakta, H. Ubiquitin-mediated regulation of 3-hydroxy-3-methylglutaryl-CoA reductase. Proc. Natl Acad. Sci. USA 94, 12944–12948 (1997).
Plemper, R. K., Egner, R., Kuchler, K. & Wolf, D. H. 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 (1998).
Hill, K. & Cooper, A. A. Degradation of unassembled Vph1p reveals novel aspects of the yeast ER quality control system. EMBO J. 19, 550–561 (2000).
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).This paper and reference 82 describe genetic screens in yeast to identify components that are involved in ER protein degradation.
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).
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).
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).This article shows that Hrd1/Der3 functions as a ubiquitin-ligase in ER-protein degradation.
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).
Plemper, R. K. 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. 112, 4123–4134 (1999).
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).
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).
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).
Breitschopf, K., Bengal, E., Ziv, T., Admon, A. & Ciechanover, A. A novel site for ubiquitination: the N-terminal residue, and not internal lysines of MyoD, is essential for conjugation and degradation of the protein. EMBO J. 17, 5964–5973 (1998).
Jarosch, E. et al. Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nature Cell Biol. 4, 134–139 (2002).
Riezman, H. The ins and outs of protein translocation. Science 278, 1728–1729 (1997).
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).
Huppa, J. B. & Ploegh, H. L. The α chain of the T cell antigen receptor is degraded in the cytosol. Immunity 7, 113–122 (1997).
Yang, M., Omura, S., Bonifacino, J. S. & Weissman, A. M. Novel aspects of degradation of T cell receptor subunits from the endoplasmic reticulum (ER) in T cells: importance of oligosaccharide processing, ubiquitination, and proteasome-dependent removal from ER membranes. J. Exp. Med. 187, 835–846 (1998).
Hirsch, C. & Ploegh, H. L. Intracellular targeting of the proteasome. Trends Cell Biol. 10, 268–272 (2000).
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).
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).
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).
Zhang, X. et al. Structure of the AAA ATPase p97. Mol. Cell 6, 1473–1484 (2000).
Patel, S. & Latterich, M. The AAA team: related ATPases with diverse functions. Trends Cell Biol. 8, 65–71 (1998).
Kondo, H. et al. p47 is a cofactor for p97-mediated membrane fusion. Nature 388, 75–78 (1997).
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).
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).
Meyer, H. H., Shorter, J. G., Seemann, J., Pappin, D. & Warren, G. A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. EMBO J. 19, 2181–2192 (2000).
Singleton, M. R., Sawaya, M. R., Ellenberger, T. & Wigley, D. B. Crystal structure of T7 gene 4 ring helicase indicates a mechanism for sequential hydrolysis of nucleotides. Cell 101, 589–600 (2000).
Schmidt, M., Lupas, A. N. & Finley, D. Structure and mechanism of ATP-dependent proteases. Curr. Opin. Chem. Biol. 3, 584–591 (1999).
Langer, T. AAA proteases: cellular machines for degrading membrane proteins. Trends Biochem. Sci. 25, 247–251 (2000).
Dai, R. M. & Li, C. C. Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin–proteasome degradation. Nature Cell Biol. 3, 740–744 (2001).
Pollard, M. G., Travers, K. J. & Weissman, J. S. Ero1p: a novel and ubiquitous protein with an essential role in oxidative protein folding in the endoplasmic reticulum. Mol. Cell 1, 171–182 (1998).
Frand, A. R. & Kaiser, C. A. The ERO1 gene of yeast is required for oxidation of protein dithiols in the endoplasmic reticulum. Mol. Cell 1, 161–170 (1998).
Acknowledgements
We thank T. Sommer, K. Matlack, H. Ploegh and D. Finley for critical reading of the manuscript and helpful comments. B.T. is a fellow of the Damon Runyon Cancer Research Foundation and Y.Y. is a Helen Hay Whitney Fellow. The work in the authors' laboratory was supported by the National Institute of Health. T.A.R. is a Howard Hughes Medical Institute Investigator.
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DATABASES
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<i>Saccharomyces</i> Genome Database
Swiss-Prot
Glossary
- CHAPERONES
-
A class of proteins that bind unfolded or partially folded polypeptides, prevent their aggregation and promote their folding.
- LYSOSOME
-
An organelle (called the vacuole in yeast) that contains many hydrolytic enzymes. Lysosomes degrade proteins that are imported into the cell by endocytosis, which are diverted to them from the secretory pathway, or taken up from the cytosol by autophagy.
- INCLUSION BODIES
-
Protein precipitates that are formed in the cytosol, often after protein overexpression.
- CARBOXYPEPTIDASE Y
-
Carboxypeptidase Y (CPY) is a protease that is transported from the endoplasmic reticulum (ER) to the vacuole of Saccharomyces cerevisiae cells. A misfolded version, CPY*, is retained in the ER, retro-translocated into the cytosol and degraded by the proteasome.
- MICROSOMES
-
A membrane fraction that consists largely of ER, and sediments slowly in the centrifuge.
- PRO-α-FACTOR
-
Pro-α-factor is the precursor of α-factor, a peptide secreted by S. cerevisiae cells for mating. In the ER lumen, pro-α-factor is generated by signal-sequence cleavage from prepro-α-factor and is glycosylated. When unglycosylated, it is misfolded, retro-translocated and degraded in the cytosol.
- [H+]ATPase
-
A plasma membrane protein, which uses the energy of ATP to pump protons out of the cell.
- APOLIPOPROTEIN
-
Lipoprotein particles have a monolayer of phospholipids at their surface, into which apolipoproteins are embedded. The latter are translocated across the ER membrane in liver cells and associate with cholesterol esters as they emerge on the lumenal side of the ER.
- β2-MICROGLOBULIN
-
A soluble, lumenal ER protein, which associates with the heavy chain of the major histocompatibility class I complex.
- AAA FAMILY OF ATPases
-
ATPases, which are associated with diverse cellular activities, contain a conserved domain of 200–250 amino acids. This domain includes Walker A and B motifs, which are required for ATP binding and hydrolysis.
- SNARE COMPLEXES
-
(SNARE, soluble N-ethylmaleimide sensitive factor attachment protein receptor). A vesicle-bound v-SNARE polypeptide associates with the three chains of a t-SNARE in the target membrane to form a stable complex, which might drive fusion of the two membranes.
- ClpP
-
A bacterial protease, which, like the eukaryotic proteasome, forms a cylinder with active sites in the interior. A ring of ATPases that is formed by ClpA feed polypeptides into ClpP.
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Tsai, B., Ye, Y. & Rapoport, T. Retro-translocation of proteins from the endoplasmic reticulum into the cytosol. Nat Rev Mol Cell Biol 3, 246–255 (2002). https://doi.org/10.1038/nrm780
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DOI: https://doi.org/10.1038/nrm780
