J. Cell Biol., Volume 142, Number 2, July 27, 1998 365-376

Dislocation of Type I Membrane Proteins from the ER to the Cytosol Is Sensitive to Changes in Redox Potential

Domenico Tortorella,^* Craig M. Story,^* Johannes B. Huppa,^* Emmanuel J.H.J. Wiertz, Thomas R. Jones,^§ and Hidde L. Ploegh^*

^* Harvard Medical School, Department of Pathology, Boston, Massachusetts 02115;  National Institute of Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands; and ^§ Department of Molecular Biology, Infectious Diseases Section, Wyeth-Ayerst Research, Pearl River, New York 10965

The human cytomegalovirus (HCMV) gene products US2 and US11 dislocate major histocompatibility class I heavy chains from the ER and target them for proteasomal degradation in the cytosol. The dislocation reaction is inhibited by agents that affect intracellular redox potential and/or free thiol status, such as diamide and N-ethylmaleimide. Subcellular fractionation experiments indicate that this inhibition occurs at the stage of discharge from the ER into the cytosol. The T cell receptor  (TCR ) chain is also degraded by a similar set of reactions, yet in a manner independent of virally encoded gene products. Diamide and N-ethylmaleimide likewise inhibit the dislocation of the full-length TCR  chain from the ER, as well as a truncated, mutant version of TCR  chain that lacks cysteine residues. Cytosolic destruction of glycosylated, ER-resident type I membrane proteins, therefore, requires maintenance of a proper redox potential for the initial step of removal of the substrate from the ER environment.

diamide;  class I heavy chain;  degradation;  human cytomegalovirus;  TCR  chain

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Oresic, K., Ng, C. L., Tortorella, D. (2009). TRAM1 Participates in Human Cytomegalovirus US2- and US11-mediated Dislocation of an Endoplasmic Reticulum Membrane Glycoprotein. J. Biol. Chem. 284: 5905-5914 [Abstract] [Full Text]  
• Ushioda, R., Hoseki, J., Araki, K., Jansen, G., Thomas, D. Y., Nagata, K. (2008). ERdj5 Is Required as a Disulfide Reductase for Degradation of Misfolded Proteins in the ER. Science 321: 569-572 [Abstract] [Full Text]  
• Oresic, K., Tortorella, D. (2008). Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules. J. Gen. Virol. 89: 1122-1130 [Abstract] [Full Text]  
• Ruddock, L. W., Molinari, M. (2006). N-glycan processing in ER quality control. J. Cell Sci. 119: 4373-4380 [Abstract] [Full Text]  
• Mueller, B., Lilley, B. N., Ploegh, H. L. (2006). SEL1L, the homologue of yeast Hrd3p, is involved in protein dislocation from the mammalian ER. JCB 175: 261-270 [Abstract] [Full Text]  
• Hassink, G. C., Barel, M. T., Van Voorden, S. B., Kikkert, M., Wiertz, E. J. (2006). Ubiquitination of MHC Class I Heavy Chains Is Essential for Dislocation by Human Cytomegalovirus-encoded US2 but Not US11. J. Biol. Chem. 281: 30063-30071 [Abstract] [Full Text]  
• Hegde, N. R., Chevalier, M. S., Wisner, T. W., Denton, M. C., Shire, K., Frappier, L., Johnson, D. C. (2006). The Role of BiP in Endoplasmic Reticulum-associated Degradation of Major Histocompatibility Complex Class I Heavy Chain Induced by Cytomegalovirus Proteins. J. Biol. Chem. 281: 20910-20919 [Abstract] [Full Text]  
• Hosokawa, N., Wada, I., Natsuka, Y., Nagata, K. (2006). EDEM accelerates ERAD by preventing aberrant dimer formation of misfolded alpha1-antitrypsin.. GENES CELLS 11: 465-476 [Abstract] [Full Text]  
• Iannello, A., Debbeche, O., Martin, E., Attalah, L. H., Samarani, S., Ahmad, A. (2006). Viral strategies for evading antiviral cellular immune responses of the host. J. Leukoc. Biol. 79: 16-35 [Abstract] [Full Text]  
• Tirosh, B., Iwakoshi, N. N., Glimcher, L. H., Ploegh, H. L. (2005). XBP-1 specifically promotes IgM synthesis and secretion, but is dispensable for degradation of glycoproteins in primary B cells. JEM 202: 505-516 [Abstract] [Full Text]  
• Wang, X., Connors, R., Harris, M. R., Hansen, T. H., Lybarger, L. (2005). Requirements for the Selective Degradation of Endoplasmic Reticulum-Resident Major Histocompatibility Complex Class I Proteins by the Viral Immune Evasion Molecule mK3. J. Virol. 79: 4099-4108 [Abstract] [Full Text]  
• Tirosh, B., Iwakoshi, N. N., Lilley, B. N., Lee, A.-H., Glimcher, L. H., Ploegh, H. L. (2005). Human Cytomegalovirus Protein US11 Provokes an Unfolded Protein Response That May Facilitate the Degradation of Class I Major Histocompatibility Complex Products. J. Virol. 79: 2768-2779 [Abstract] [Full Text]  
• Marciniak, S. J., Yun, C. Y., Oyadomari, S., Novoa, I., Zhang, Y., Jungreis, R., Nagata, K., Harding, H. P., Ron, D. (2004). CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18: 3066-3077 [Abstract] [Full Text]  
• Fiebiger, E., Hirsch, C., Vyas, J. M., Gordon, E., Ploegh, H. L., Tortorella, D. (2004). Dissection of the Dislocation Pathway for Type I Membrane Proteins with a New Small Molecule Inhibitor, Eeyarestatin. Mol. Biol. Cell 15: 1635-1646 [Abstract] [Full Text]  
• Furman, M. H., Loureiro, J., Ploegh, H. L., Tortorella, D. (2003). 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 [Abstract] [Full Text]  
• Hegde, N. R., Johnson, D. C. (2003). Human Cytomegalovirus US2 Causes Similar Effects on Both Major Histocompatibility Complex Class I and II Proteins in Epithelial and Glial Cells. J. Virol. 77: 9287-9294 [Abstract] [Full Text]  
• Lilley, B. N., Tortorella, D., Ploegh, H. L. (2003). Dislocation of a Type I Membrane Protein Requires Interactions between Membrane-spanning Segments within the Lipid Bilayer. Mol. Biol. Cell 14: 3690-3698 [Abstract] [Full Text]  
• Chevalier, M. S., Johnson, D. C. (2003). Human Cytomegalovirus US3 Chimeras Containing US2 Cytosolic Residues Acquire Major Histocompatibility Class I and II Protein Degradation Properties. J. Virol. 77: 4731-4738 [Abstract] [Full Text]  
• Tirosh, B., Furman, M. H., Tortorella, D., Ploegh, H. L. (2003). Protein Unfolding Is Not a Prerequisite for Endoplasmic Reticulum-to-Cytosol Dislocation. J. Biol. Chem. 278: 6664-6672 [Abstract] [Full Text]  
• Cunnea, P. M., Miranda-Vizuete, A., Bertoli, G., Simmen, T., Damdimopoulos, A. E., Hermann, S., Leinonen, S., Huikko, M. P., Gustafsson, J.-A., Sitia, R., Spyrou, G. (2003). ERdj5, an Endoplasmic Reticulum (ER)-resident Protein Containing DnaJ and Thioredoxin Domains, Is Expressed in Secretory Cells or following ER Stress. J. Biol. Chem. 278: 1059-1066 [Abstract] [Full Text]  
• Molinari, M., Galli, C., Piccaluga, V., Pieren, M., Paganetti, P. (2002). Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER. JCB 158: 247-257 [Abstract] [Full Text]  
• Chevalier, M. S., Daniels, G. M., Johnson, D. C. (2002). Binding of Human Cytomegalovirus US2 to Major Histocompatibility Complex Class I and II Proteins Is Not Sufficient for Their Degradation. J. Virol. 76: 8265-8275 [Abstract] [Full Text]  
• Lorenzo, M. E., Jung, J. U., Ploegh, H. L. (2002). Kaposi's Sarcoma-Associated Herpesvirus K3 Utilizes the Ubiquitin-Proteasome System in Routing Class I Major Histocompatibility Complexes to Late Endocytic Compartments. J. Virol. 76: 5522-5531 [Abstract] [Full Text]  
• VanSlyke, J. K., Musil, L. S. (2002). Dislocation and degradation from the ER are regulated by cytosolic stress. JCB 157: 381-394 [Abstract] [Full Text]  
• Gewurz, B. E., Ploegh, H. L., Tortorella, D. (2002). US2, a Human Cytomegalovirus-encoded Type I Membrane Protein, Contains a Non-cleavable Amino-terminal Signal Peptide. J. Biol. Chem. 277: 11306-11313 [Abstract] [Full Text]  
• Ben-Arieh, S. V., Zimerman, B., Smorodinsky, N. I., Yaacubovicz, M., Schechter, C., Bacik, I., Gibbs, J., Bennink, J. R., Yewdell, J. W., Coligan, J. E., Firat, H., Lemonnier, F., Ehrlich, R. (2001). Human Cytomegalovirus Protein US2 Interferes with the Expression of Human HFE, a Nonclassical Class I Major Histocompatibility Complex Molecule That Regulates Iron Homeostasis. J. Virol. 75: 10557-10562 [Abstract] [Full Text]  
• Gewurz, B. E., Wang, E. W., Tortorella, D., Schust, D. J., Ploegh, H. L. (2001). Human Cytomegalovirus US2 Endoplasmic Reticulum-Lumenal Domain Dictates Association with Major Histocompatibility Complex Class I in a Locus-Specific Manner. J. Virol. 75: 5197-5204 [Abstract] [Full Text]  
• Zhong, G., Fan, P., Ji, H., Dong, F., Huang, Y. (2001). Identification of a Chlamydial Protease-like Activity Factor Responsible for the Degradation of Host Transcription Factors. JEM 193: 935-942 [Abstract] [Full Text]  
• WANG, T.-G., GOTOH, Y., JENNINGS, M. H., RHOADS, C. A., AW, T. Y. (2000). Lipid hydroperoxide-induced apoptosis in human colonic CaCo-2 cells is associated with an early loss of cellular redox balance. FASEB J. 14: 1567-1576 [Abstract] [Full Text]  
• Karaivanova, V. K., Spiro, R. G. (2000). Effect of proteasome inhibitors on the release into the cytosol of free polymannose oligosaccharides from glycoproteins. Glycobiology 10: 727-735 [Abstract] [Full Text]  
• Suzuki, T., Park, H., Hollingsworth, N. M., Sternglanz, R., Lennarz, W. J. (2000). PNG1, a Yeast Gene Encoding a Highly Conserved Peptide:N-glycanase. JCB 149: 1039-1052 [Abstract] [Full Text]  
• MANCINI, R., FAGIOLI, C., FRA, A. M., MAGGIONI, C., SITIA, R. (2000). Degradation of unassembled soluble Ig subunits by cytosolic proteasomes: evidence that retrotranslocation and degradation are coupled events. FASEB J. 14: 769-778 [Abstract] [Full Text]  
• Cabibbo, A., Pagani, M., Fabbri, M., Rocchi, M., Farmery, M. R., Bulleid, N. J., Sitia, R. (2000). ERO1-L, a Human Protein That Favors Disulfide Bond Formation in the Endoplasmic Reticulum. J. Biol. Chem. 275: 4827-4833 [Abstract] [Full Text]  
• Chillarón, J., Haas, I. G. (2000). Dissociation from BiP and Retrotranslocation of Unassembled Immunoglobulin Light Chains Are Tightly Coupled to Proteasome Activity. Mol. Biol. Cell 11: 217-226 [Abstract] [Full Text]  
• Gillece, P., Luz, J. M., Lennarz, W. J., de la Cruz, F. J., Romisch, K. (1999). Export of a Cysteine-free Misfolded Secretory Protein from the Endoplasmic Reticulum for Degradation Requires Interaction with Protein Disulfide Isomerase. JCB 147: 1443-1456 [Abstract] [Full Text]  
• Shamu, C. E., Story, C. M., Rapoport, T. A., Ploegh, H. L. (1999). The Pathway of US11-dependent Degradation of MHC Class I Heavy Chains Involves a Ubiquitin-conjugated Intermediate. JCB 147: 45-58 [Abstract] [Full Text]  
• Story, C. M., Furman, M. H., Ploegh, H. L. (1999). The cytosolic tail of class I MHC heavy chain is required for its dislocation by the human cytomegalovirus US2 and US11 gene products. Proc. Natl. Acad. Sci. USA 96: 8516-8521 [Abstract] [Full Text]  
• Kokura, S., Wolf, R. E., Yoshikawa, T., Granger, D. N., Aw, T. Y. (1999). Molecular Mechanisms of Neutrophil-Endothelial Cell Adhesion Induced by Redox Imbalance. Circ. Res. 84: 516-524 [Abstract] [Full Text]  
• Romisch, K (1999). Surfing the Sec61 channel: bidirectional protein translocation across the ER membrane. J. Cell Sci. 112: 4185-4191 [Abstract]  
• Fagioli, C., Mezghrani, A., Sitia, R. (2001). Reduction of Interchain Disulfide Bonds Precedes the Dislocation of Ig-{micro} Chains from the Endoplasmic Reticulum to the Cytosol for Proteasomal Degradation. J. Biol. Chem. 276: 40962-40967 [Abstract] [Full Text]  
• Furman, M. H., Ploegh, H. L., Tortorella, D. (2002). Membrane-specific, Host-derived Factors Are Required for US2- and US11-mediated Degradation of Major Histocompatibility Complex Class I Molecules. J. Biol. Chem. 277: 3258-3267 [Abstract] [Full Text]  
• VanSlyke, J. K., Musil, L. S. (2002). Dislocation and degradation from the ER are regulated by cytosolic stress. JCB 157: 381-394 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents