Herpes Simplex Virus 1 γ134.5 Protein Inhibits STING Activation That Restricts Viral Replication
Herpes Simplex Virus 1 γ134.5 Protein Inhibits STING Activation That Restricts Viral Replication
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DOI：
10.1128/jvi.01015-18
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发表时间：
2018-10-01
影响因子：
5.4
通讯作者：
He, Bin
中科院分区：
文献类型：
--
作者：
Pan, Shuang;Liu, Xing;He, Bin
单纯疱疹病毒1（HSV-1）的γ（1）34.5基因编码促进病毒发病的毒力因子。尽管它会扰乱先天免疫途径复杂网络中的TANK结合激酶1（TBK 1），但其潜在机制尚不清楚。在这里，我们报告了HSV-1 gamma（1）34.5在调节TBK 1激活的细胞内DNA识别途径中靶向干扰素基因刺激物（STING）。在病毒感染的细胞中，γ（1）34.5蛋白与STING结合并使其失活，这导致干扰素调节因子3（IRF 3）和IFN应答的下调。重要的是，HSV-1 gamma（1）34.5破坏STING从内质网到高尔基体的易位，这是引发细胞免疫所必需的过程。从HSV-1中删除γ（1）34.5或其氨基末端结构域可消除观察到的抑制活性。一致地，缺乏功能性γ（1）34.5的HSV突变体在STING（+/+）中的复制效率低于在STING（-/-）小鼠胚胎成纤维细胞中。此外，在STING（-/-）细胞中重建的人STING表达激活IRF 3并减少病毒生长。这些结果表明，γ（1）34.5对DNA传感通路的控制有利于HSV感染。重要性病毒对先天免疫的抑制有助于单纯疱疹病毒的发病机制。虽然这一复杂的过程涉及多种因素，但其背后的事件仍不清楚。我们证明了HSV毒力因子γ（1）34.5排除了STING的激活，STING是细胞内DNA传感途径中的一个中心适配器。在HSV感染后，这种病毒蛋白与STING结合并使其失活。因此，它损害宿主免疫力并促进HSV复制。这些观察揭示了可能介导病毒毒力的HSV机制。
The gamma(1)34.5 gene of herpes simplex virus 1 (HSV-1) encodes a virulence factor that promotes viral pathogenesis. Although it perturbs TANK-binding kinase 1 (TBK1) in the complex network of innate immune pathways, the underlying mechanism is obscure. Here we report that HSV-1 gamma(1)34.5 targets stimulator of interferon genes (STING) in the intracellular DNA recognition pathway that regulates TBK1 activation. In virus-infected cells the gamma(1)34.5 protein associates with and inactivates STING, which leads to downregulation of interferon regulatory factor 3 (IRF3) and IFN responses. Importantly, HSV-1 gamma(1)34.5 disrupts translocation of STING from the endoplasmic reticulum to Golgi apparatus, a process necessary to prime cellular immunity. Deletion of gamma(1)34.5 or its amino-terminal domain from HSV-1 abolishes the observed inhibitory activities. Consistently, an HSV mutant that lacks functional gamma(1)34.5 replicated less efficiently in STING(+/+) than in STING(-/-) mouse embryonic fibroblasts. Moreover, reconstituted expression of human STING in the STING(-/-) cells activated IRF3 and reduced viral growth. These results suggest that control of the DNA sensing pathway by gamma(1)34.5 is advantageous to HSV infection.IMPORTANCE Viral inhibition of innate immunity contributes to herpes simplex virus pathogenesis. Although this complex process involves multiple factors, the underlying events remain unclear. We demonstrate that an HSV virulence factor gamma(1)34.5 precludes the activation of STING, a central adaptor in the intracellular DNA sensing pathway. Upon HSV infection, this viral protein engages with and inactivates STING. Consequently, it compromises host immunity and facilitates HSV replication. These observations uncover an HSV mechanism that is likely to mediate viral virulence.