Interferon-independent STING signaling promotes resistance to HSV-1 in vivo

Lívia H. Yamashiro, Stephen C. Wilson, Huntly M. Morrison, Vasiliki Karalis, Jing-Yi J. Chung, Katherine J. Chen, Helen S. Bateup, Moriah L. Szpara, Angus Y. Lee, Jeffery S. Cox and Russell E. Vance ()
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Lívia H. Yamashiro: University of California
Stephen C. Wilson: University of California
Huntly M. Morrison: University of California
Vasiliki Karalis: University of California
Jing-Yi J. Chung: University of California
Katherine J. Chen: University of California
Helen S. Bateup: University of California
Moriah L. Szpara: Pennsylvania State University
Angus Y. Lee: University of California
Jeffery S. Cox: University of California
Russell E. Vance: University of California

Nature Communications, 2020, vol. 11, issue 1, 1-11

Abstract: Abstract The Stimulator of Interferon Genes (STING) pathway initiates potent immune responses upon recognition of DNA. To initiate signaling, serine 365 (S365) in the C-terminal tail (CTT) of STING is phosphorylated, leading to induction of type I interferons (IFNs). Additionally, evolutionary conserved responses such as autophagy also occur downstream of STING, but their relative importance during in vivo infections remains unclear. Here we report that mice harboring a serine 365-to-alanine (S365A) mutation in STING are unexpectedly resistant to Herpes Simplex Virus (HSV)-1, despite lacking STING-induced type I IFN responses. By contrast, resistance to HSV-1 is abolished in mice lacking the STING CTT, suggesting that the STING CTT initiates protective responses against HSV-1, independently of type I IFNs. Interestingly, we find that STING-induced autophagy is a CTT- and TBK1-dependent but IRF3-independent process that is conserved in the STING S365A mice. Thus, interferon-independent functions of STING mediate STING-dependent antiviral responses in vivo.

Date: 2020
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DOI: 10.1038/s41467-020-17156-x

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