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J. Biol. Chem., Vol. 281, Issue 13, 8636-8644, March 31, 2006

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The Viral E3 Ubiquitin Ligase mK3 Uses the Derlin/p97 Endoplasmic Reticulum-associated Degradation Pathway to Mediate Down-regulation of Major Histocompatibility Complex Class I Proteins^*

Xiaoli Wang, Yihong Ye, Wayne Lencer^¶, and Ted H. Hansen¹

From the Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, the Laboratory of Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, and ^¶Gastrointestinal Cell Biology, Children's Hospital Boston, the Harvard Digestive Diseases Center, Boston, Massachusetts 02115

Ubiquitin E3 ligases are important cellular components for endoplasmic reticulum (ER)-associated degradation due to their role in substrate-specific ubiquitination, which is required for retrotranslocation (dislocation) of most unwanted proteins from the ER to the cytosol for proteasome degradation. However, our understanding of the molecular mechanisms of how E3 ligases confer substrate-specific recognition, and their role in substrate retrotranslocation is limited especially in mammalian cells. mK3 is a type III ER membrane protein encoded by murine herpesvirus 68. As conferred by its N-terminal RING-CH domain, mK3 has E3 ubiquitin ligase activity. In its role as an immune evasion protein, mK3 specifically targets nascent major histocompatibility complex class I heavy chains (HC) for rapid degradation. The mechanism by which mK3 extracts HC from the ER membrane into the cytosol for proteasome-mediated degradation is unknown. Evidence is presented here that HC down-regulation by mK3 is dependent on the p97 AAA-ATPase. By contrast, the kK5 protein of Kaposi's sarcoma-associated herpesvirus is p97-independent despite the fact that it is highly homologous to mK3. mK3 protein was also found in physical association with Derlin1, an ER protein recently implicated in the retrotranslocation of HC by immune evasion protein US11, but not US2, of human cytomegalovirus. The mechanistic implications of these findings are discussed.

Received for publication, December 30, 2005 , and in revised form, January 26, 2006.

^* This work was supported by National Institutes of Health Grant AI19687. 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 Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-2716; Fax: 314-362-4137; E-mail: hansen{at}immunology.wustl.edu.

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