Differential regulation of K8 gene expression in immediate-early and delayed-early stages of Kaposi's sarcoma-associated herpesvirus.

KSHV-encoded bZip protein, namely K8, is a regulatory protein with multiple functions in immediate-early and delayed-early stages of viral life cycle. Here we report that K8 gene is expressed in both immediate-early and delayed-early phases and the transcription in different phases is controlled by distinct promoters, yielding two transcripts, an immediate-early mRNA of 1.5 kb and a delayed-early mRNA of 1.3 kb. The transcription from the immediate-early promoter is inducible by sodium butyrate or 12-O-tetradecanoylphorbol-13-acetate (TPA), but not responsive to ORF50 (Rta). The delayed-early promoter of K8 shows little response to sodium butyrate and TPA, but can be fully induced by ORF50 (Rta). In the immediate-early promoter, a 20-bp region containing two consensus Sp-1 binding sites was found to be crucial for the basal transcription and sodium butyrate induction of the promoter. In addition, mutagenesis analyses identified three ORF50 (Rta) responsive elements (RREs) in the delayed-early promoter and their roles in ORF50-dependent transactivation were investigated. The differential regulation of K8 gene expression may represent a strategy in that the virus fine-tunes the levels of K8 protein in different stages or for distinct functions. The elucidation of K8 gene expression regulation helps in understanding roles of K8 in viral replication and pathogenicity.