NF-κB serves as a cellular sensor of Kaposi's sarcoma-associated herpesvirus latency and negatively regulates K-Rta by antagonizing the RBP-Jκ coactivator

Yoshihiro Izumiya, Chie Izumiya, Datsun Hsia, Thomas J. Ellison, Paul A. Luciw, Hsing Jien Kung

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45 Citations (Scopus)

Abstract

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-κB 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-κB expression was induced. Many K-Rta-responsive promoters modulated by NF-κB contain the sequence of the RBP-Jκ binding site, a major coactivator which anchors K-Rta to target promoters via consensus motifs which overlap with that of NF-κB. Gel shift assays demonstrated that NF-κB inhibits the binding of RBP-Jκ and forms a complex with RBP-Jκ. Our results support a model in which a balance between K-Rta/RBP-Jκ and NF-κB activities determines KSHV reactivation. An important feature of this model is that the interplay between RBP-Jκ and NF-κB on viral promoters controls viral gene expression mediated by K-Rta.

Original languageEnglish
Pages (from-to)4435-4446
Number of pages12
JournalJournal of Virology
Volume83
Issue number9
DOIs
Publication statusPublished - May 1 2009
Externally publishedYes

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ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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