State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China 430072.
Medical Research Institute, Collaborative Innovation Center for Viral Immunology, School of Medicine, Wuhan University, Wuhan, China 430071.
Cell Host Microbe. 2017 Feb 8;21(2):231-243. doi: 10.1016/j.chom.2017.01.001. Epub 2017 Jan 26.
Recognition of human cytomegalovirus (HCMV) DNA by the cytosolic sensor cGAS initiates STING-dependent innate antiviral responses. HCMV can antagonize host immune responses to promote latency infection. However, it is unknown whether and how HCMV targets the cGAS-STING axis for immune evasion. Here we identified the HCMV tegument protein UL82 as a negative regulator of STING-dependent antiviral responses. UL82 interacted with STING and impaired STING-mediated signaling via two mechanisms. UL82 inhibited the translocation of STING from the ER to perinuclear microsomes by disrupting the STING-iRhom2-TRAPβ translocation complex. UL82 also impaired the recruitment of TBK1 and IRF3 to the STING complex. The levels of downstream antiviral genes induced by UL82-deficient HCMV were higher than those induced by wild-type HCMV. Conversely, wild-type HCMV replicated more efficiently than the UL82-deficient mutant. These findings reveal an important mechanism of immune evasion by HCMV.
人巨细胞病毒（HCMV）DNA 通过细胞质传感器 cGAS 的识别，引发 STING 依赖性先天抗病毒反应。HCMV 可以拮抗宿主免疫反应，促进潜伏感染。然而，尚不清楚 HCMV 是否以及如何针对 cGAS-STING 轴进行免疫逃避。在这里，我们鉴定出 HCMV 被膜蛋白 UL82 是 STING 依赖性抗病毒反应的负调节剂。UL82 与 STING 相互作用，并通过两种机制损害 STING 介导的信号转导。UL82 通过破坏 STING-iRhom2-TRAPβ 易位复合物，抑制 STING 从内质网到核周微体的易位。UL82 还损害了 TBK1 和 IRF3 到 STING 复合物的募集。由 UL82 缺失 HCMV 诱导的下游抗病毒基因的水平高于由野生型 HCMV 诱导的水平。相反，野生型 HCMV 的复制效率高于 UL82 缺失突变体。这些发现揭示了 HCMV 免疫逃避的一个重要机制。
