The ER-Associated Protein ZDHHC1 Is a Positive Regulator of DNA Virus-Triggered, MITA/STING-Dependent Innate Immune Signaling
The ER-Associated Protein ZDHHC1 Is a Positive Regulator of DNA Virus-Triggered, MITA/STING-Dependent Innate Immune Signaling
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DOI：
10.1016/j.chom.2014.09.006
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发表时间：
2014-10-08
影响因子：
30.3
通讯作者：
Wang, Yan-Yi
中科院分区：
文献类型：
--
作者：
Zhou, Qian;Lin, Heng;Wang, Yan-Yi
感染细胞的胞质溶胶内的病毒DNA感应激活I型干扰素（IFN）表达。MITA/STING通过充当第二信使cGAMP的传感器和下游信号传导组分的适配器在该途径中起着重要作用。在一个可以激活IFNB 1启动子的蛋白质的表达筛选中，我们鉴定了ER相关蛋白ZDHHC 1作为病毒触发的MITA/STING依赖性免疫信号传导的正调节因子。Zdhhc 1（-/-）细胞不能有效地产生IFN和其他细胞因子，以响应DNA而不是RNA病毒的感染。Zdhhc 1（-/-）小鼠感染嗜神经DNA病毒HSV-1后，脑内细胞因子水平降低，病毒滴度升高，导致致死率升高。ZDHHC 1与MITA/STING组成型相关，并介导MITA/STING的二聚化/聚集以及下游信号传导组分TBK 1和IRF 3的募集。这些发现支持ZDHHC 1在介导针对DNA病毒的MITA/STING依赖性先天免疫应答中的作用。
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.