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

doi:10.1083/jcb.142.2.365

A correction to this article has been published: J. Cell Biol. 145 (3) 643

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© The Rockefeller University Press, 0021-9525/1998//365 $5.00
The Journal of Cell Biology, Volume 142, Number 2, , 1998 365-376

Articles

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 US11dislocate major histocompatibility class I heavy chains fromthe ER and target them for proteasomal degradation in the cytosol.The dislocation reaction is inhibited by agents that affectintracellular redox potential and/or free thiol status, suchas diamide and N-ethylmaleimide. Subcellular fractionationexperiments indicate that this inhibition occurs at the stageof discharge from the ER into the cytosol. The T cell receptor ${alpha}$ (TCR ${alpha}$ ) 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 dislocationof the full-length TCR ${alpha}$ chain from the ER, as well as a truncated,mutant version of TCR ${alpha}$ chain that lacks cysteine residues.Cytosolic destruction of glycosylated, ER-resident type I membrane proteins, therefore, requires maintenance of a proper redoxpotential for the initial step of removal of the substratefrom the ER environment.

Key Words: diamide • class I heavy chain • degradation • human cytomegalovirus • TCR ${alpha}$ chain

Abbreviations used in this paper: CPY, carboxypeptidase Y; diamide, diazenedicarboxylic acid bis(N,N-dimethylamide); HCMV, human cytomegalovirus; IAA, iodoacetic acid; IAM, iodoacetamide; IEF, isoelectric focusing; MHC, major histocompatibility complex; NEM, N-ethylmaleimide; PDI, protein disulfide isomerase; TCR, T cell receptor; ZL₃H, carboxylbenzyl-leucyl-leucyl-leucinal; ZL₃VS, carboxylbenzyl-leucyl-leucyl-leucyl vinylsulfone.

Domenico Tortorella is supported by a fellowship from The Irvington Institute for Immunological Research (New York). Craig M. Storyis supported by a Cancer Research Institute Fellowship (NewYork). Johannes B. Huppa was supported by the Boehringer IngelheimFonds (Stuttgart, Germany). This work was supported by theNational Institutes of Health and Boehringer-Ingelheim Pharmaceuticals,Inc.

Address all correspondence to Hidde L. Ploegh, Harvard MedicalSchool, Department of Pathology, 200 Longwood Avenue, Boston,MA 02139. Tel.: (617) 432-4776. Fax: (617) 432-4775. E-mail:ploegh{at}hms.harvard.edu

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