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

• Published in: The Journal of cell biology 1998-07, Vol.142 (2), p.365-376
• Main Authors: Tortorella, Domenico, Story, Craig M., Huppa, Johannes B., Emmanuel J. H. J. Wiertz, Jones, Thomas R., Ploegh, Hidde L.
• Format: Article
• Language: English
• Subjects: Cell Line; Cell lines; Cells; Cellular biology; COS cells; Cytomegalovirus - genetics; Cytomegalovirus - immunology; Cytomegalovirus - metabolism; Cytosol; Cytosol - immunology; Cytosol - metabolism; Cytosol - virology; Diamide - pharmacology; Disulfides; Endoplasmic Reticulum - immunology; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - virology; Ethylmaleimide - pharmacology; Glycosylation; Histocompatibility Antigens Class I - chemistry; Histocompatibility Antigens Class I - metabolism; Humans; Membrane proteins; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Membranes; Molecular chains; Molecules; Oxidation-Reduction; Protein Folding; Proteins; Receptors, Antigen, T-Cell, alpha-beta - genetics; Receptors, Antigen, T-Cell, alpha-beta - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Sequence Deletion; T cell antigen receptors; T lymphocytes; Viral Proteins - genetics; Viral Proteins - metabolism
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.142.2.365

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 α (TCR α) 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 α chain from the ER, as well as a truncated, mutant version of TCR α 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.