Host Cellular responses accompanied by Epstein-Barr Virus genome replication.

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Induction of the Epstein-Barr virus(EBV) lytic program elicits ATM-dependent DNA damage response, resulting in phosphorylation of p53 at Ser15, which, prevents interaction with MDM2. Nevertheless, p53-downstream signaling is blocked. We found here that during the lytic infection p53 was actively degraded in a proteasome-dependent manner even with a reduced level of MDM2. Turnover of p53 was stimulated in the lytic phase compared with that in the latent phase, indicating that EBV regulates p53 level also after induction of the lytic replication. Co-immunoprecipitation analysis revealed that the EBV BZLF1 immediate-early protein interacted with the DNA-binding domain near the N-terminus of p53. It was confirmed that BZLF1 protein elicited proteasome-dependent degradation of p53. and repressed the p53-mediated transactivation in SaOS-2 cells. The degradation of p53 was observed even in the presence of Nutlin-3, an inhibitor of p53-MDM2 interaction, and also in mouse embryo fibroblasts lacking mdm2 gene, indicating that the BZLF1 protein-induced degradation of p53 was independent of MDM2. Furthermore, Nutlin-3 increased the level of p53 in the latent phase of EBV infection but not in the lytic phase. Thus, although p53 level is regulated by MDM2 in the latent phase, it might be mediated by the BZLF1 protein-associated E3 ubiquitin ligase in the lytic phase, providing the insight that EBV regulates the cellular environment advantageous for lytic replication through degradation of p53, leading to inhibition of p53 downstream signaling pathway.