Epstein-Barr virus immediate-early proteins BZLF1 and BRLF1 activate the ATF2 transcription factor by increasing the levels of phosphorylated p38 andc-Jun N-terminal kinases

Expression of either Epstein-Barr virus (EBV) immediate-early protein BZLF1 (Z) or BRLF1 (R) is sufficient to convert EBV infection from the latent to lytic form. Disruption of viral latency requires transcriptional activatio n of the Z and R promoters. The Z and R proteins are transcriptional activa tors, and each immediate-early protein activates expression of the other im mediate-early protein. Z activates the R promoter through a direct binding mechanism, However, R does not bind directly to the Z promoter. In this stu dy, we demonstrate that the ZII element (a cyclic AMP response element site ) in the Z promoter is required for efficient activation by R The ZII eleme nt has been shown to be important for induction of lytic EBV infection by t etradecanoyl phorbol acetate and surface immunoglobulin cross-linking and i s activated by Z through an indirect mechanism. We demonstrate that both R and Z activate the cellular stress mitogen-activated protein (MAP) kinases, p38 and JNK, resulting in phosphorylation (and activation) of the cellular transcription factor ATF2. Furthermore, we show that the ability of R to i nduce lytic EBV infection in latently infected cells is significantly reduc ed by inhibition of either the p38 kinase or JNK pathway. In contrast, inhi bition of stress MAP kinase pathways does not impair the ability of Z expre ssion vectors to disrupt viral latency, presumably because expression of Z under the control of a strong heterologous promoter bypasses the need to ac tivate Z transcription. Thus, both R and Z can activate the Z promoter indi rectly by inducing ATF2 phosphorylation, and this activity appears to be im portant for R-induced disruption of viral latency.