Medical Research Institute, College of Life Sciences, Wuhan University, Wuhan 430072, China.
State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430072, China.
Cell Host Microbe. 2014 Oct 8;16(4):450-61. doi: 10.1016/j.chom.2014.09.006.
Viral DNA sensing within the cytosol of infected cells activates type I interferon (IFN) expression. MITA/STING plays an essential role in this pathway by acting as both a sensor for the second messenger cGAMP and as an adaptor for downstream signaling components. In an expression screen for proteins that can activate the IFNB1 promoter, we identified the ER-associated protein ZDHHC1 as a positive regulator of virus-triggered, MITA/STING-dependent immune signaling. Zdhhc1(-/-) cells failed to effectively produce IFNs and other cytokines in response to infection with DNA but not RNA viruses. Zdhhc1(-/-) mice infected with the neurotropic DNA virus HSV-1 exhibited lower cytokine levels and higher virus titers in the brain, resulting in higher lethality. ZDHHC1 constitutively associated with MITA/STING and mediates dimerization/aggregation of MITA/STING and recruitment of the downstream signaling components TBK1 and IRF3. These findings support a role for ZDHHC1 in mediating MITA/STING-dependent innate immune response against DNA viruses.
细胞质中受感染细胞内的病毒 DNA 感应会激活 I 型干扰素（IFN）表达。MITA/STING 通过充当第二信使 cGAMP 的传感器以及下游信号成分的衔接子，在该途径中发挥重要作用。在一个用于筛选可激活 IFNB1 启动子的蛋白质的表达筛选中，我们鉴定出 ER 相关蛋白 ZDHHC1 是病毒触发的、MITA/STING 依赖性免疫信号的正向调节剂。在 DNA 但不是 RNA 病毒感染时，Zdhhc1(-/-)细胞无法有效地产生 IFN 和其他细胞因子。感染神经嗜性 DNA 病毒 HSV-1 的 Zdhhc1(-/-) 小鼠在大脑中的细胞因子水平较低，病毒滴度较高，导致死亡率较高。ZDHHC1 与 MITA/STING 持续相关，并介导 MITA/STING 的二聚体/聚集以及下游信号成分 TBK1 和 IRF3 的募集。这些发现支持 ZDHHC1 在介导针对 DNA 病毒的 MITA/STING 依赖性先天免疫反应中的作用。
