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J. Biol. Chem., Vol. 282, Issue 34, 24858-24865, August 24, 2007

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Kaposi's Sarcoma-associated Herpesvirus (KSHV) Oncoprotein K13 Bypasses TRAFs and Directly Interacts with the IB Kinase Complex to Selectively Activate NF-B without JNK Activation^*

Hittu Matta, Lucia Mazzacurati, Sandra Schamus, Tianbing Yang, Qinmiao Sun^¶, and Preet M. Chaudhary¹

From the Department of Medicine, Division of Hematology-Oncology and the Translational Research Core Facility, Hillman Cancer Center, The University of Pittsburgh, Pittsburgh, Pennsylvania 15213 and the ^¶Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8593

Kaposi's sarcoma herpesvirus oncoprotein vFLIP K13 is a potent activator of NF-B and plays a key role in viral pathogenesis. K13 contains a putative TRAF-interacting motif, which is reportedly required for its interaction with TRAF2. The K13-TRAF2 interaction is believed to be essential for the recruitment of K13 to the I-B kinase (IKK) complex and for K13-induced NF-B and JNK activation. In addition, TRAF3 has been reported to be required for K13-induced NF-B and JNK activation. We have re-examined the role of the TRAFs in K13 signaling and report that mutations in the putative TRAF-interacting motif of K13 have no deleterious effect on its ability to interact with the IKK complex or activation of the NF-B pathway. Furthermore, endogenously expressed TRAF2 and TRAF3 do not interact with K13 and play no role in K13-induced NF-B activation or its interaction with the IKK complex. Finally, K13 does not activate the JNK pathway. Our results support a model in which K13 bypasses the upstream components of the tumor necrosis factor receptor signaling pathway and directly interacts with the IKK complex to selectively activate the NF-B pathway without affecting the JNK pathway. Selective NF-B activation by K13 might represent a novel strategy employed by the virus to promote latency.

Received for publication, January 4, 2007 , and in revised form, May 14, 2007.

^* This work was supported in part by Grant CA85177 from the National Institutes of Health and grants from the Leukemia & Lymphoma Society and the Mario Lemieux Foundation. 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: Hillman Cancer Center, 5117 Centre Ave., Suite 1.19A, Pittsburgh, PA 15213-1863. Tel.: 412-623-7703; Fax: 412-623-1415; E-mail: chaudharypm{at}upmc.edu.

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