Liang Xiaozhen, Pickering Mary T, Cho Nam-Hyuk, Chang Heesoon, Volkert Michael R, Kowalik Timothy F, Jung Jae U
Department of Microbiology and Molecular Genetics, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
J Virol. 2006 Jun;80(12):5862-74. doi: 10.1128/JVI.02732-05.
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 (gammaHV68) 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 gammaHV68 M2 blocks apoptosis-mediated intracellular innate immunity, which might ultimately contribute to its role in latent infection.
受感染细胞将病毒复制识别为一种DNA损伤应激，并引发DNA损伤反应，该反应最终诱导细胞凋亡，作为宿主免疫监视的一部分。在此，我们展示了一种新机制，即鼠γ疱疹病毒68（γHV68）的潜伏期相关抗干扰素M2蛋白通过与DDB1/COP9/ Cul1修复复合物和ATM DNA损伤信号转导器相互作用，抑制DNA损伤诱导的细胞凋亡。在没有DNA损伤的情况下，M2的表达持续诱导DDB1的核定位和ATM激酶激活。激活的ATM随后诱导Chk激活以及p53磷酸化和稳定，而在DNA损伤时不会引发H2AX磷酸化和MRN募集到病灶。因此，M2的表达抑制了DNA修复，使细胞对DNA损伤诱导的细胞凋亡产生抗性，并诱导G1期细胞周期停滞。我们的结果表明，γHV68 M2阻断了凋亡介导的细胞内固有免疫，这可能最终有助于其在潜伏感染中的作用。
