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The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER

¹ Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England, UK
² University Medical Centre Utrecht, 3584 CX Utrecht, Netherlands
³ Division of Hematology/Oncology, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425

Correspondence to Paul J. Lehner: pjl30{at}cam.ac.uk

The US2 and US11 gene products of human cytomegalovirus promote viral evasion by hijacking the endoplasmic reticulum (ER)–associated degradation (ERAD) pathway. US2 and US11 initiate dislocation of newly translocated major histocompatibility complex class I (MHC I) from the ER to the cytosol for proteasome-mediated degradation, thereby decreasing cell surface MHC I. Despite being instrumental in elucidating the mammalian ERAD pathway, the responsible E3 ligase or ligases remain unknown. Using a functional small interfering RNA library screen, we now identify TRC8 (translocation in renal carcinoma, chromosome 8 gene), an ER-resident E3 ligase previously implicated as a hereditary kidney cancer gene, as required for US2-mediated MHC I ubiquitination. Depletion of TRC8 prevents MHC I ubiquitination and dislocation by US2 and restores cell surface MHC I. TRC8 forms an integral part of a novel multiprotein ER complex that contains MHC I, US2, and signal peptide peptidase. Our data show that the TRC8 E3 ligase is required for MHC I dislocation from the ER and identify a new complex associated with mammalian ERAD.

Abbreviations used in this paper: ERAD, ER-associated degradation; MHC I, major histocompatibility complex class I; RING, really interesting new gene; shRNA, short hairpin RNA; SPP, signal peptide peptidase.

© 2009 Stagg et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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This article has been cited by other articles:

• Stagg, H. R., Thomas, M., van den Boomen, D., Wiertz, E. J.H.J., Drabkin, H. A., Gemmill, R. M., Lehner, P. J. (2009). The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER. JEM 206: i22-i22 [Full Text]  
• Leslie, M. (2009). Cytomegalovirus sticks it to MHC. JCB 186: 632-632 [Full Text]  

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