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J. Biol. Chem., Vol. 281, Issue 30, 20910-20919, July 28, 2006

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The Role of BiP in Endoplasmic Reticulum-associated Degradation of Major Histocompatibility Complex Class I Heavy Chain Induced by Cytomegalovirus Proteins^*

Nagendra R. Hegde, Mathieu S. Chevalier, Todd W. Wisner, Michael C. Denton, Kathy Shire, Lori Frappier, and David C. Johnson¹

From the Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon 97239 and the Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Human cytomegalovirus (HCMV1) US11 and US2 proteins cause rapid degradation of major histocompatibility complex (MHC) molecules, apparently by ligating cellular endoplasmic reticulum (ER)-associated degradation machinery. Here, we show that US11 and US2 bind the ER chaperone BiP. Four related HCMV proteins, US3, US7, US9, and US10, which do not promote degradation of MHC proteins, did not bind BiP. Silencing BiP reduced US11- and US2-mediated degradation of MHC class I heavy chain (HC) without altering the synthesis or translocation of HC into the ER or the stability of HC in the absence of US11 or US2. Induction of the unfolded protein response (UPR) did not affect US11-mediated HC degradation and could not explain the stabilization of HC when BiP was silenced. Unlike in yeast, BiP did not act by maintaining substrates in a retrotranslocation-competent form. Our studies go beyond previous observations in mammalian cells correlating BiP release with degradation, demonstrating that BiP is functionally required for US2- and US11-mediated HC degradation. Further, US2 and US11 bound BiP even when HC was absent and degradation of US2 depended on HC. These data were consistent with a model in which US2 and US11 bridge HC onto BiP promoting interactions with other ER-associated degradation proteins.

Received for publication, March 29, 2006 , and in revised form, May 24, 2006.

^* This work was supported by Grants EY11245 and AI055051 from the National Institutes of Health (to D. C. J.) and from the Canadian Institutes of Health Research (to L. F.). 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 To whom correspondence should be addressed: Dept. of Molecular Microbiology & Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Tel.: 503-494-0834; Fax: 503-494-6862; E-mail: johnsoda{at}ohsu.edu.

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