CREB-binding protein and histone deacetylase regulate the transcriptional activity of Kaposi's sarcoma-associated herpesvirus open reading frame 50

Kaposi's sarcoma (KS)-associated herpesvirus (KSKV) open reading frame 50 ( ORF50) encodes a viral transcriptional activator, which binds to the KSHV p romoter and stimulates the transcription of viral early and late genes, thu s activating the lytic cycle of KSHV. We report here that KSHV ORF50 binds to the cellular proteins CREB-binding protein (CBP) and histone deacetylase (HDAC) and these binding events modulate ORF50-activated viral transcripti on. Binding of ORF50 to CBP and HDAC activates and represses, respectively, ORF50 mediated viral transcription. KSHV ORF50 was shown to bind to the C/ H3 domain and the C-terminal transcriptional activation domain of CBP, whil e CBP bound to the amino-terminal basic domain and the carboxyl-terminal tr ansactivation domain of ORF50. The LXXLL motif within the transcriptional a ctivation domain of ORF50 is reminiscent of the CBP-binding sequence found in nuclear receptor proteins. The adenovirus E1A protein, which also binds to the C/H3 domain of CBP, repressed the transcriptional activation activit y of ORF50. The cellular protein c-Jun, which binds to the kinase-induced a ctivation domain of ORF50, stimulated ORF50-mediated viral transcription. T he HDAC1-interacting domain of ORF50 was shown to be a central proline-rich sequence. Our data provide a framework for delineating the regulatory mech anisms used by KSHV to modulate its transcription and replication through i nteraction with both histone acetyltransferases and HDACs.