Viral oncoprotein LMP1 disrupts p53-induced cell cycle arrest and apoptosis through modulating K63-linked ubiquitination of p53
Viral oncoprotein LMP1 disrupts p53-induced cell cycle arrest and apoptosis through modulating K63-linked ubiquitination of p53
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DOI：
10.4161/cc.20771
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发表时间：
2012-06-15
期刊：
影响因子：
4.3
通讯作者：
Cao, Ya
中科院分区：
文献类型：
--
作者：
Li, Lili;Li, Wei;Cao, Ya
看门人p53肿瘤抑制因子的破坏涉及各种病毒相关的肿瘤发生，其中异常泛素化是病毒相关肿瘤中p53异常的主要原因。值得注意的是，野生型p53在EB病毒（EBV）相关肿瘤中积累，特别是在鼻咽癌（NPC）中。我们以前已经发现p53在NPC中被EB病毒癌蛋白潜伏膜蛋白1（LMP 1）积累和磷酸化。在这里，我们进一步发现LMP 1通过两种不同的泛素修饰促进p53积累。LMP 1通过抑制由E3连接酶MDM 2介导的K48-连接的p53泛素化，同时增加总细胞泛素化p53的水平，从而促进p53的稳定性和积累，所述泛素化与其在Ser 20的磷酸化相关。LMP 1还通过与肿瘤坏死因子受体相关因子2（TRAF 2）相互作用诱导K63连接的p53泛素化，从而促进p53积累。此外，LMP 1挽救了由K63连接的p53泛素化介导的肿瘤细胞凋亡和细胞周期停滞。总的来说，这些结果证明了病毒蛋白LMP 1对p53及其生物学功能的异常泛素修饰，这对多种EBV相关肿瘤的发病机制具有广泛的意义。
Disruption of the gatekeeper p53 tumor suppressor is involved in various virus-associated tumorigeneses, with aberrant ubiquitination as the major cause of p53 abnormalities in virus-associated tumors. Of note, wild-type p53 is accumulated in Epstein-Barr virus (EBV)-associated tumors, especially in nasopharyngeal carcinoma (NPC). We have previously identified that p53 is accumulated and phosphorylated by EBV oncoprotein latent membrane protein 1 (LMP1) in NPC. Here, we further found that LMP1 promoted p53 accumulation via two distinct ubiquitin modifications. LMP1 promoted p53 stability and accumulation by suppressing K48-linked ubiquitination of p53 mediated by E3 ligase MDM2, which is associated with its phosphorylation at Ser20, while increasing the levels of total cellular ubiquitinated p53. LMP1 also induced K63-linked ubiquitination of p53 by interacting with tumor necrosis factor receptor-associated factor 2 (TRAF2), thus contributing to p53 accumulation. Furthermore, LMP1 rescued tumor cell apoptosis and cell cycle arrest mediated by K63-linked ubiquitination of p53. Collectively, these results demonstrate aberrant ubiquitin modifications of p53 and its biological functions by viral protein LMP1, which has broad implications to the pathogenesis of multiple EBV-associated tumors.