Sato Yoshitaka, Shirata Noriko, Kudoh Ayumi, Iwahori Satoko, Nakayama Sanae, Murata Takayuki, Isomura Hiroki, Nishiyama Yukihiro, Tsurumi Tatsuya
Division of Virology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Virology. 2009 May 25;388(1):204-11. doi: 10.1016/j.virol.2009.03.017. Epub 2009 Apr 16.
The Epstein-Barr virus (EBV) lytic program elicits ATM-dependent DNA damage response, resulting in phosphorylation of p53 at N-terminus, 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. BZLF1 protein enhanced the ubiquitination of p53 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. 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 for efficient viral propagation.
爱泼斯坦-巴尔病毒（EBV）的裂解程序引发了依赖ATM的DNA损伤反应，导致p53在N端磷酸化，从而阻止其与MDM2相互作用。然而，p53的下游信号传导被阻断。我们在此发现，在裂解感染期间，即使MDM2水平降低，p53仍以蛋白酶体依赖的方式被积极降解。BZLF1蛋白增强了SaOS-2细胞中p53的泛素化。即使存在p53-MDM2相互作用抑制剂Nutlin-3，以及在缺乏mdm2基因的小鼠胚胎成纤维细胞中，也观察到了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感染的潜伏期增加了p53的水平，但在裂解期没有增加。虽然在潜伏期p53水平受MDM2调节，但在裂解期可能由BZLF1蛋白相关的E3泛素连接酶介导，以实现有效的病毒传播。
