Degradation of phosphorylated p53 by viral protein-ECS E3 ligase complex.
Degradation of phosphorylated p53 by viral protein-ECS E3 ligase complex.
复制标题
DOI：
10.1371/journal.ppat.1000530
复制
发表时间：
2009-07
期刊：
影响因子：
6.7
通讯作者：
Tsurumi T
中科院分区：
文献类型：
--
作者：
Sato Y;Kamura T;Shirata N;Murata T;Kudoh A;Iwahori S;Nakayama S;Isomura H;Nishiyama Y;Tsurumi T
p53-信号传导被病毒调节以建立有利于其繁殖的宿主细胞环境。EB病毒（EBV）裂解程序诱导p53的磷酸化，其阻止与MDM 2的相互作用。在这里，我们表明，诱导EBV裂解程序导致降解p53通过泛素-蛋白酶体途径独立于MDM 2。BZLF 1蛋白直接作为ECS（Elongin B/C-Cul 2/5-SOCS-box蛋白）泛素连接酶复合物的衔接子组分发挥作用，靶向p53以降解。令人费解的是，由病毒裂解复制引起的活化DNA损伤反应引起的p53的C-末端磷酸化增强了其与BZLF 1蛋白的结合。纯化的BZLF 1蛋白相关的ECS在体外可以比野生型更有效地催化磷酸模拟p53的泛素化。在裂解性感染的中期和晚期阶段的p53的补偿抑制裂解性感染期间的病毒DNA复制和产生，这表明p53的降解是有效的病毒繁殖所需的。综上所述，这些研究结果证明了BZLF 1蛋白相关的ECS连接酶复合物在病毒裂解感染期间通过激活DNA损伤信号调节p53磷酸化中的作用。抑制p53介导的反式激活对于调节有利于病毒感染的细胞环境是必不可少的。特别地，DNA病毒通过泛素-蛋白酶体途径靶向p53以使其失活。高危型人乳头瘤病毒的E6蛋白和细胞内的泛素-蛋白连接酶E6 AP形成复合物，引起p53的泛素化和降解。腺病毒E1 B 55-kDa蛋白与p53和E4 orf 6结合，并募集含有Cullin的复合物来指导泛素介导的p53蛋白水解。然而，与较小的DNA病毒的作用相比，关于EB病毒（EBV）抑制p53功能的精确机制知之甚少。EBV具有两个可选择的生命周期，潜伏复制和裂解复制。在潜伏期，p53由MDM 2泛素连接酶调节，而在诱导裂解性复制后，p53被磷酸化，活化的p53的水平由独立于MDM 2的新系统调节。这份报告描述了一个独特的功能作用的BZLF 1蛋白编码的EBV在激活的p53的调制。在该途径中，BZLF 1蛋白作为含Cul 2和Cul 5的E3泛素连接酶复合物的接头分子，刺激p53的泛素化和降解，从而抑制细胞凋亡，表明EBV机制中的冗余下调p53水平。因此，有可能复合物不仅调节p53，而且调节与BZLF 1蛋白相互作用的各种蛋白。
p53-signaling is modulated by viruses to establish a host cellular environment advantageous for their propagation. The Epstein-Barr virus (EBV) lytic program induces phosphorylation of p53, which prevents interaction with MDM2. Here, we show that induction of EBV lytic program leads to degradation of p53 via an ubiquitin-proteasome pathway independent of MDM2. The BZLF1 protein directly functions as an adaptor component of the ECS (Elongin B/C-Cul2/5-SOCS-box protein) ubiquitin ligase complex targeting p53 for degradation. Intringuingly, C-terminal phosphorylation of p53 resulting from activated DNA damage response by viral lytic replication enhances its binding to BZLF1 protein. Purified BZLF1 protein-associated ECS could be shown to catalyze ubiquitination of phospho-mimetic p53 more efficiently than the wild-type in vitro. The compensation of p53 at middle and late stages of the lytic infection inhibits viral DNA replication and production during lytic infection, suggesting that the degradation of p53 is required for efficient viral propagation. Taken together, these findings demonstrate a role for the BZLF1 protein-associated ECS ligase complex in regulation of p53 phosphorylated by activated DNA damage signaling during viral lytic infection. Inhibition of p53-mediated transactivation is essential for regulating the cellular environment advantageous for viral infection. Specially, DNA viruses target p53 for inactivation through the ubiquitin-proteasome pathway. The E6 protein of the high-risk human papillomaviruses and the cellular ubiquitin-protein ligase E6AP form a complex which causes ubiquitination and degradation of p53. The adenovirus E1B 55-kDa protein binds to both p53 and E4orf6, and recruits a Cullin-containing complex to direct the ubiquitin-mediated proteolysis of p53. However, in comparison with the effects of the smaller DNA viruses, much less is known regarding the precise mechanisms whereby the Epstein-Barr virus (EBV) inhibits functions of p53. EBV possesses two alternative life cycles, latent and lytic replication. In latent phase, p53 is regulated by MDM2 ubiquitin ligase while after induction of lytic replication p53 is phosphorylated and the level of activated p53 is regulated by a novel system independent of MDM2. This report describes a unique functional role of the BZLF1 protein encoded by EBV in the modulation of activated p53. In this pathway, BZLF1 protein serves as an adaptor molecule for both Cul2- and Cul5-containing E3 ubiquitin ligase complexes to stimulate the ubiquitination and degradation of p53 for inhibiting apoptosis, indicating redundancy in the EBV machinery to downregulate p53 level. Therefore, it would be possible that the complexes regulate not only p53 but also various proteins that interact with BZLF1 protein.