Abstract:
:The γ134.5 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 γ134.5 targets stimulator of interferon genes (STING) in the intracellular DNA recognition pathway that regulates TBK1 activation. In virus-infected cells the γ134.5 protein associates with and inactivates STING, which leads to downregulation of interferon regulatory factor 3 (IRF3) and IFN responses. Importantly, HSV-1 γ134.5 disrupts translocation of STING from the endoplasmic reticulum to Golgi apparatus, a process necessary to prime cellular immunity. Deletion of γ134.5 or its amino-terminal domain from HSV-1 abolishes the observed inhibitory activities. Consistently, an HSV mutant that lacks functional γ134.5 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 γ134.5 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 γ134.5 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.
journal_name
J Viroljournal_title
Journal of virologyauthors
Pan S,Liu X,Ma Y,Cao Y,He Bdoi
10.1128/JVI.01015-18subject
Has Abstractpub_date
2018-09-26 00:00:00issue
20eissn
0022-538Xissn
1098-5514pii
JVI.01015-18journal_volume
92pub_type
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