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J. Biol. Chem., Vol. 282, Issue 37, 26845-26856, September 14, 2007

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Dislocation of an Endoplasmic Reticulum Membrane Glycoprotein Involves the Formation of Partially Dislocated Ubiquitinated Polypeptides^*

From the Mount Sinai School of Medicine, Department of Microbiology, New York, New York 10029

Accumulation of improperly folded polypeptides in the endoplasmic reticulum (ER) can trigger a stress response that leads to the export of aberrant proteins into the cytosol and their ultimate proteasomal degradation. Human cytomegalovirus encodes a type I glycoprotein, US11, that binds to nascent MHC class I heavy chain molecules and causes their dislocation from the ER to the cytosol where they are degraded by the proteasome. Examination of US11-mediated class I degradation has identified a host of cellular proteins involved in the dislocation reaction, including the cytosolic AAA ATPase p97, the membrane protein Derlin-1, and the E3 ubiquitin ligase Sel1L. However, the intermediate steps occurring between the initiation of dislocation and full extraction of the misfolded substrate into the cytosol are not known. We demonstrate that US11 itself undergoes ER export and proteasomal degradation and utilize this system to define multiple steps of US11 dislocation. Treatment of US11-expressing cells with proteasome inhibitor resulted in the accumulation of glycosylated and ubiquitinated species as well as a deglycosylated US11 intermediate. Subcellular fractionation of proteasome-inhibited US11 cells demonstrated that deglycosylated intermediates continued to be integrated within the ER membrane, suggesting that the proteasome functions in the latter steps of dislocation. The data supports a model in which US11 is modified with ubiquitin, whereas the transmembrane region is integrated in the ER membrane, and deglycosylation occurs before complete dislocation.

Received for publication, May 25, 2007 , and in revised form, July 19, 2007.

^* This work was supported in part in part by National Institutes of Health Grant AI060905. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A pre-doctoral trainee and supported in part by United States Public Health Service Institutional Research Training Award AI07647.

² To whom correspondence should be addressed: Dept. of Microbiology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1124 New York, NY 10029. Tel.: 212-241-5447; Fax: 212-241-7336; E-mail: domenico.tortorella{at}mssm.edu.

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