Department of Molecular Biology, Princeton University, Washington Road, Princeton, NJ 08544, USA.
Cell Host Microbe. 2013 Nov 13;14(5):591-9. doi: 10.1016/j.chom.2013.10.007.
Nuclear sensing of viral DNA has emerged as an essential step in innate immune responses against herpesviruses. Here, we provide mechanistic insight into host recognition of human cytomegalovirus (HCMV) and subsequent immune evasion by this prominent DNA virus. We establish that the interferon-inducible protein IFI16 acts as a nuclear DNA sensor following HCMV infection, binding viral DNA and triggering expression of antiviral cytokines via the STING-TBK1-IRF3 signaling pathway. The HCMV tegument protein pUL83 inhibits this response by interacting with the IFI16 pyrin domain, blocking its oligomerization upon DNA sensing and subsequent immune signals. pUL83 disrupts IFI16 by concerted action of its N- and C-terminal domains, in which an evolutionarily conserved N-terminal pyrin association domain (PAD) binds IFI16. Additionally, phosphorylation of the N-terminal domain modulates pUL83-mediated inhibition of pyrin aggregation. Collectively, our data elucidate the interplay between host DNA sensing and HCMV immune evasion, providing targets for restoring antiviral immunity.
病毒 DNA 的核感应已成为固有免疫反应对抗疱疹病毒的重要步骤。在这里，我们提供了宿主对人巨细胞病毒 (HCMV) 的识别以及该主要 DNA 病毒随后进行免疫逃避的机制见解。我们确定干扰素诱导蛋白 IFI16 在 HCMV 感染后作为核 DNA 传感器发挥作用，结合病毒 DNA 并通过 STING-TBK1-IRF3 信号通路触发抗病毒细胞因子的表达。HCMV 被膜蛋白 pUL83 通过与 IFI16 的吡喃结构域相互作用来抑制这种反应，阻止其在 DNA 感应后寡聚化和随后的免疫信号。pUL83 通过其 N 端和 C 端结构域的协同作用破坏 IFI16，其中进化上保守的 N 端吡喃关联结构域 (PAD) 与 IFI16 结合。此外，N 端结构域的磷酸化调节 pUL83 介导的吡喃聚集抑制。总的来说，我们的数据阐明了宿主 DNA 感应与 HCMV 免疫逃避之间的相互作用，为恢复抗病毒免疫提供了靶标。
