Adenovirus 12 E4orf6 inhibits ATR activation by promoting TOPBP1 degradation
Adenovirus 12 E4orf6 inhibits ATR activation by promoting TOPBP1 degradation
复制标题
DOI：
10.1073/pnas.0914605107
复制
发表时间：
2010-07-06
影响因子：
11.1
通讯作者：
Turnell, Andrew S.
中科院分区：
文献类型：
--
作者：
Blackford, Andrew N.;Patel, Rakesh N.;Turnell, Andrew S.
激活细胞DNA损伤反应对腺病毒(Ad)感染是不利的。因此，AD已经进化出许多策略来在感染期间抑制依赖ATM和ATR的信号通路。最近的研究表明，Ad5 E4orf3蛋白通过错误定位MRN复合体的能力来阻止ATR激活。在这里，我们提供的证据表明，AD12已经进化出一种与Ad5不同的策略来抑制ATR。我们发现AD12利用含有CUL2/RBX1/细长蛋白C的泛素连接酶来促进ATR激活蛋白拓扑异构酶-IIβ结合蛋白1(TOPBP1)的蛋白酶体降解。AD12也使用这种复合体在感染期间降解p53，而Ad5需要基于CUL5的泛素连接酶。虽然AD12介导的P53降解依赖于E1B-55K和E4orf6，但AD12介导的TOPBP1降解仅依赖E4orf6。我们认为AD12 E4orf6有两个主要活性：招募基于CUL2的泛素连接酶和作为TOPBP1的底物受体。为了支持AD12 E4orf6通过靶向TOPBP1降解来特异性阻止ATR在感染过程中激活的想法，我们证明了AD12 E4orf6可以抑制复制应激反应中依赖ATR的CHK1的磷酸化。综上所述，这些数据为Ad在感染过程中如何调节ATR信号通路提供了洞察力。
Activation of the cellular DNA damage response is detrimental to adenovirus (Ad) infection. Ad has therefore evolved a number of strategies to inhibit ATM- and ATR-dependent signaling pathways during infection. Recent work suggests that the Ad5 E4orf3 protein prevents ATR activation through its ability to mislocalize the MRN complex. Here we provide evidence to indicate that Ad12 has evolved a different strategy from Ad5 to inhibit ATR. We show that Ad12 utilizes a CUL2/RBX1/elongin C-containing ubiquitin ligase to promote the proteasomal degradation of the ATR activator protein topoisomerase-II beta-binding protein 1 (TOPBP1). Ad12 also uses this complex to degrade p53 during infection, in contrast to Ad5, which requires a CUL5-based ubiquitin ligase. Although Ad12-mediated degradation of p53 is dependent upon both E1B-55K and E4orf6, Ad12-mediated degradation of TOPBP1 is solely dependent on E4orf6. We propose that Ad12 E4orf6 has two principal activities: to recruit the CUL2-based ubiquitin ligase and to act as substrate receptor for TOPBP1. In support of the idea that Ad12 E4orf6 specifically prevents ATR activation during infection by targeting TOPBP1 for degradation, we demonstrate that Ad12 E4orf6 can inhibit the ATR-dependent phosphorylation of CHK1 in response to replication stress. Taken together, these data provide insights into how Ad modulates ATR signaling pathways during infection.