Adenovirus oncoprotein E4orf6 triggers Cullin5 neddylation to activate the CLR5 E3 ligase for p53 degradation
Adenovirus oncoprotein E4orf6 triggers Cullin5 neddylation to activate the CLR5 E3 ligase for p53 degradation
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腺病毒癌蛋白 E4orf6 触发 Cullin5 neddylation 激活 CLR5 E3 连接酶以降解 p53
DOI：
10.1016/j.bbrc.2019.07.028
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发表时间：
2019-09-03
影响因子：
3.1
通讯作者：
Wei, Wei
中科院分区：
文献类型：
--
作者：
Guo, Haoran;Shen, Siyu;Wei, Wei
人腺病毒癌蛋白E4orf6劫持细胞内基于cullin 5的E3泛素连接酶(CRL5s)，诱导宿主蛋白(包括P53)的降解，从而阻碍病毒的有效复制。该复合体还依赖于另一种病毒蛋白E1B55K来招募泛素化的底物。然而，腺病毒E4orf6-CRL5 E3连接酶介导的P53在支架蛋白Cullin5中降解的决定因素仍然很少被研究。在这里，我们证明了病毒蛋白E4orf6引发了Cullin5蛋白从细胞质到细胞核的重新定位，并通过促进核内连接诱导了CRL5 E3连接酶的激活。E4orf6显著下调DENP8/Den1的表达。然后，我们确定SENP8是E4orf6诱导的P53降解的自然限制因子。此外，我们的结果表明，NEDD8结合的E2酶UBE2M对于E4orf6介导的P53的降解是必不可少的，其显性负突变UBE2M C111S显著阻断了E4orf6的功能。Nedd8激活酶抑制剂MLN4924减少了E4orf6诱导的cullin5蛋白的缺失，随后抑制了P53的降解。总之，我们的发现阐明了这种病毒癌蛋白特异性地利用核苷酸途径激活宿主CRL E3连接酶以降解宿主限制因子的策略。干扰这种翻译后修饰是对抗人腺病毒的一种有吸引力的药理学干预。(C)2019 Elsevier Inc.保留所有权利。
The human adenovirus oncoprotein E4orf6 hijacks intracellular Cullin 5-based E3 ubiquitin ligases (CRL5s) to induce the degradation of host proteins, including p53, that impede efficient viral replication. The complex also relies on another viral protein, E1B55K, to recruit substrates for ubiquitination. However, the determinants of adenoviral E4orf6-CRL5 E3 ligase-mediated p53 degradation in the scaffolding protein Cullin5 remain rarely investigated. Here, we demonstrated that the viral protein E4orf6 triggered relocalization of the Cullin5 protein from the cytoplasm to the nucleus and induced activation of the CRL5 E3 ligase via facilitating neddylation. The expression of the deneddylase SENP8/Den1 was significantly downregulated by E4orf6. We then identified SENP8 as a natural restriction factor for E4orf6-induced p53 degradation. Furthermore, our results indicated that the NEDD8-conjugating E2 enzyme UBE2M was essential for E4orf6-mediated p53 degradation and that its dominant negative mutant UBE2M C111S dramatically blocked E4orf6 functions. The Nedd8-activating enzyme inhibitor MLN4924 decreased E4orf6-induced neddylation of the cullin5 protein and subsequently suppressed p53 degradation. Collectively, our findings illuminate the strategy by which this viral oncoprotein specifically utilizes the neddylation pathway to activate host CRL E3 ligases to degrade host restriction factors. Disrupting this post-translational modification is an attractive pharmacological intervention against human adenoviruses. (C) 2019 Elsevier Inc. All rights reserved.