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

Epstein-Barr病毒（EBV）裂解程序的诱导引起atm依赖的DNA损伤反应，导致p53的Ser15磷酸化，从而阻止与MDM2的相互作用。然而，p53下游信号被阻断。我们在这里发现，在裂解性感染期间，p53以蛋白酶体依赖的方式被积极降解，即使MDM2水平降低。与潜伏期相比，p53的转换在裂解期被刺激，表明EBV在诱导裂解复制后也调节p53的水平。共免疫沉淀分析显示EBV BZLF1即早蛋白与p53 n端附近的dna结合域相互作用。证实BZLF1蛋白引发蛋白酶体依赖性p53降解。并抑制p53介导的SaOS-2细胞的转激活。即使在p53- mdm2相互作用抑制剂Nutlin-3存在的情况下，以及缺乏mdm2基因的小鼠胚胎成纤维细胞中，也可以观察到p53的降解，这表明BZLF1蛋白诱导的p53降解不依赖于mdm2。此外，Nutlin-3在EBV感染潜伏期增加p53水平，而在溶解期不增加p53水平。因此，尽管p53水平在潜伏期受MDM2调控，但在裂解期可能受BZLF1蛋白相关E3泛素连接酶的介导，从而揭示EBV通过降解p53调控有利于裂解复制的细胞环境，从而抑制p53下游信号通路。

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.