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Journal of Virology, May 2009, p. 4435-4446, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.01999-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

NF-{kappa}B Serves as a Cellular Sensor of Kaposi's Sarcoma-Associated Herpesvirus Latency and Negatively Regulates K-Rta by Antagonizing the RBP-J{kappa} Coactivator{triangledown}

Yoshihiro Izumiya,1,2* Chie Izumiya,2 Datsun Hsia,2 Thomas J. Ellison,2 Paul A. Luciw,3 and Hsing-Jien Kung2

Department of Dermatology,1 Department of Biological Chemistry, University of California, Davis School of Medicine, UC Davis Cancer Center, Sacramento, California 95817,2 Center for Comparative Medicine and Department of Pathology, University of California, Davis, Davis, California 956163

Received 22 September 2008/ Accepted 16 February 2009

Successful viral replication is dependent on a conducive cellular environment; thus, viruses must be sensitive to the state of their host cells. We examined the idea that an interplay between viral and cellular regulatory factors determines the switch from Kaposi's sarcoma-associated herpesvirus (KSHV) latency to lytic replication. The immediate-early gene product K-Rta is the first viral protein expressed and an essential factor in reactivation; accordingly, this viral protein is in a key position to serve as a viral sensor of cellular physiology. Our approach aimed to define a host transcription factor, i.e., host sensor, which modulates K-Rta activity on viral promoters. To this end, we developed a panel of reporter plasmids containing all 83 putative viral promoters for a comprehensive survey of the response to both K-Rta and cellular transcription factors. Interestingly, members of the NF-{kappa}B family were shown to be strong negative regulators of K-Rta transactivation for all but two viral promoters (Ori-RNA and K12). Recruitment of K-Rta to the ORF57 and K-bZIP promoters, but not the K12 promoter, was significantly impaired when NF-{kappa}B expression was induced. Many K-Rta-responsive promoters modulated by NF-{kappa}B contain the sequence of the RBP-J{kappa} binding site, a major coactivator which anchors K-Rta to target promoters via consensus motifs which overlap with that of NF-{kappa}B. Gel shift assays demonstrated that NF-{kappa}B inhibits the binding of RBP-J{kappa} and forms a complex with RBP-J{kappa}. Our results support a model in which a balance between K-Rta/RBP-J{kappa} and NF-{kappa}B activities determines KSHV reactivation. An important feature of this model is that the interplay between RBP-J{kappa} and NF-{kappa}B on viral promoters controls viral gene expression mediated by K-Rta.

* Corresponding author. Mailing address: UC Davis Cancer Center, Research III Room 2400B, 4645 2nd Avenue, Sacramento, CA 95817. Phone: (916) 734-7842. Fax: (916) 734-2589. E-mail: yizumiya{at}ucdavis.edu

{triangledown} Published ahead of print on 25 February 2009.

Journal of Virology, May 2009, p. 4435-4446, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.01999-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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