Deregulation of DNA damage signal transduction by herpesvirus latency-associated M2
Deregulation of DNA damage signal transduction by herpesvirus latency-associated M2
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DOI：
10.1128/jvi.02732-05
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发表时间：
2006-06-01
影响因子：
5.4
通讯作者：
Jung, Jae U.
中科院分区：
文献类型：
--
作者：
Liang, Xiaozhen;Pickering, Mary T.;Jung, Jae U.
感染细胞将病毒复制识别为DNA损伤应激，并引发DNA损伤应答，最终诱导细胞凋亡，作为宿主免疫监视的一部分。在这里，我们证明了一种新的机制，小鼠γ疱疹病毒68（γ HV 68）潜伏相关的，抗干扰素M2蛋白抑制DNA损伤诱导的细胞凋亡的DDB 1/COP 9/cullin修复复合物和ATM DNA损伤信号转导的相互作用。在没有DNA损伤的情况下，M2表达组成型诱导DDB 1核定位和ATM激酶活化。活化的ATM随后诱导Chk活化和p53磷酸化和稳定化，而不引发H2 AX磷酸化和MRN募集到DNA损伤后的病灶。因此，M2表达抑制DNA修复，使细胞对DNA损伤诱导的凋亡产生抗性，并诱导G（1）细胞周期停滞。我们的研究结果表明，γ HV 68 M2块骨化介导的细胞内先天免疫，这可能最终有助于其在潜伏感染中的作用。
Infected cells recognize viral replication as a DNA damage stress and elicit a DNA damage response that ultimately induces apoptosis as part of host immune surveillance. Here, we demonstrate a novel mechanism where the murine gamma herpesvirus 68 (gamma HV68) latency-associated, anti-interferon M2 protein inhibits DNA damage-induced apoptosis by interacting with the DDB1/COP9/cullin repair complex and the ATM DNA damage signal transducer. M2 expression constitutively induced DDB1 nuclear localization and ATM kinase activation in the absence of DNA damage. Activated ATM subsequently induced Chk activation and p53 phosphorylation and stabilization without eliciting H2AX phosphorylation and MRN recruitment to foci upon DNA damage. Consequently, M2 expression inhibited DNA repair, rendered cells resistant to DNA damage-induced apoptosis, and induced a G(1) cell cycle arrest. Our results suggest that gamma HV68 M2 blocks apoptosis-mediated intracellular innate immunity, which might ultimately contribute to its role in latent infection.