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J. Biol. Chem., Vol. 278, Issue 49, 48942-48949, December 5, 2003

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Interaction of Epstein-Barr Virus Latent Membrane Protein 1 with SCF^HOS/-TrCP E3 Ubiquitin Ligase Regulates Extent of NF-B Activation^*

Weigang Tang, Oleg A. Pavlish, Vladimir S. Spiegelman¶||, Andrey A. Parkhitko, and Serge Y. Fuchs**

From the Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, Laboratory of Viral Carcinogenesis, Cancer Research Center, Russian Academy of Medical Sciences, Moscow 115478, Russia, and ^¶AMC Cancer Center, Lakewood, Colorado 80214

The Epstein-Barr virus latent membrane protein 1 (LMP1) is pivotal in the transforming activity of this virus. We found that the common LMP1-95-8 variant interacts with Homologue of Slimb (HOS), a receptor for the SCF^HOS/TrCP ubiquitin-protein isopeptide ligase (E3) via one canonical and one cryptic HOS recognition site. These sites are mutated or deleted in the tumor-derived LMP1-Cao variant, which did not bind to HOS. Mutations within these sites on LMP1-95-8 abrogated HOS binding and increased transforming activity of LMP1. HOS did not regulate stability of LMP1-95-8 unless it was mutated to bear additional lysine residues near the cryptic motif. LMP1 proteins that could not bind to HOS exhibited an increased ability to induce IB degradation and NF-B-mediated transcription without further increase in activation of IB kinases. Expression of LMP1-95-8 reduced the levels of endogenous HOS available to interact with phosphorylated IB. Degradation of IB and dose dependence of NF-B activation by LMP1-95-8 were promoted by co-expression of HOS. Our data suggest that LMP1-95-8 is a pseudo-substrate of SCF^HOS/TrCP E3 ubiquitin ligase and that interaction between LMP1 and HOS restricts the extent of LMP1-induced NF-B signaling. We discuss the potential role of this mechanism in transforming and cytostatic effects of LMP1 variants in cells and Epstein-Barr virus-associated tumors.

Received for publication, July 22, 2003 , and in revised form, September 22, 2003.

^* This work was supported in part by NCI Grant CA 92900 from the National Institutes of Health (to S. Y. F.) and by Russian Federation Research Foundation Grant 02-04-49510 (to O. A. P). 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.

^|| Supported by American Cancer Society Award RSG-02-140-01-CNE.

^** To whom correspondence should be addressed: Dept. of Animal Biology, University of Pennsylvania, 3800 Spruce St., Rm. 161E, Philadelphia, PA 19104-6046. Tel.: 215-573-6949; Fax: 215-573-5188; E-mail: sfuks{at}vet.upenn.edu.

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