Herpes Simplex Virus 1 γ 1 34.5 Protein Inhibits STING Activation That Restricts Viral Replication

• Published in: Journal of virology 2018-10, Vol.92 (20)
• Main Authors: Pan, Shuang, Liu, Xing, Ma, Yijie, Cao, Youjia, He, Bin
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Chlorocebus aethiops; Down-Regulation; Gene Deletion; Genetic Complementation Test; Herpesvirus 1, Human - immunology; Herpesvirus 1, Human - physiology; Host-Pathogen Interactions; Humans; Immune Evasion; Interferon Regulatory Factor-3 - biosynthesis; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Mice; Mice, Knockout; Viral Proteins - genetics; Viral Proteins - metabolism; Virulence Factors - genetics; Virulence Factors - metabolism; Virus Replication
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.01015-18

The γ 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 γ 34.5 targets stimulator of interferon genes (STING) in the intracellular DNA recognition pathway that regulates TBK1 activation. In virus-infected cells the γ 34.5 protein associates with and inactivates STING, which leads to downregulation of interferon regulatory factor 3 (IRF3) and IFN responses. Importantly, HSV-1 γ 34.5 disrupts translocation of STING from the endoplasmic reticulum to Golgi apparatus, a process necessary to prime cellular immunity. Deletion of γ 34.5 or its amino-terminal domain from HSV-1 abolishes the observed inhibitory activities. Consistently, an HSV mutant that lacks functional γ 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 γ 34.5 is advantageous to HSV infection. 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 γ 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.