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J. Biol. Chem., Vol. 279, Issue 37, 38325-38330, September 10, 2004

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ORF36 Protein Kinase of Kaposi's Sarcoma Herpesvirus Activates the c-Jun N-terminal Kinase Signaling Pathway^*

M. Sabry Hamza, Richard A. Reyes, Yoshihiro Izumiya, Ronald Wisdom¶, Hsing-Jien Kung, and Paul A. Luciw||**

From the Center for Comparative Medicine, the Department of Biological Chemistry and Cancer Center, the ^¶Division of Hematology and Oncology, and the ^||Department of Pathology, University of California, Davis, California 95616

-, -, and -Herpesviruses encode putative viral protein kinases. The herpes simplex virus UL13, varicella-zoster virus ORF47, and Epstein-Barr virus BGLF4 genes all show protein kinase domains in their protein sequences. Mutational analysis of these herpesviruses demonstrated that the viral kinase is important for optimal virus growth. Previous studies have shown that ORF36 of Kaposi's sarcoma herpesvirus (KSHV) has protein kinase activity and is autophosphorylated on serine. The gene for ORF36 is expressed during lytic growth of the virus and has been classified as a late gene. Inspection of the ORF36 sequence indicated potential motifs that could be involved in activation of cellular transcription factors. To analyze the function of ORF36, the cDNA for this viral gene was tagged with the FLAG epitope and inserted into an expression vector for mammalian cells. Transfection experiments in 293T and SLK cells demonstrated that expression of ORF36 resulted in phosphorylation of the c-Jun N-terminal kinase. Autophosphorylation of ORF36 is important for JNK activation because a mutation in the predicted catalytic domain of ORF36 blocked its ability to phosphorylate JNK. Western blot analysis, using phosphospecific antibodies, revealed that mitogen-activated kinases MKK4 and MKK7 were phosphorylated by ORF36 but not by the kinase-negative mutant. Binding experiments in transfected cells also demonstrated that both the wild type and kinase-negative mutant of ORF36 form a complex with JNK, MKK4, and MKK7. In addition, using a tetracycline-inducible Rta BCBL-1 cell line (TREx BCBL1-Rta), JNK was phosphorylated during lytic replication, and inhibition of JNK activation blocked late viral gene expression but not early viral gene expression. In summary, these studies demonstrate that KSHV ORF36 activates the JNK pathway; thus this cell signaling pathway may function in the KSHV life cycle by regulating viral and/or cellular transcription.

Received for publication, January 28, 2004 , and in revised form, June 16, 2004.

^* This work was supported by NCI, National Institutes of Health Grant CA91574 (to H.-J. K.), California Universitywide AIDS Research Program Grant R00-D-034 (to H.-J. K.), and National Center for Research Resources Grant RR00169 (to P. A. L.). 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.

^** To whom correspondence should be addressed. Tel.: 530-752-3430; Fax: 530-752-7914; E-mail: paluciw{at}ucdavis.edu.

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