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

  • Author(s): Yamashiro, Lívia H
  • Wilson, Stephen C
  • Morrison, Huntly M
  • Karalis, Vasiliki
  • Chung, Jing-Yi J
  • Chen, Katherine J
  • Bateup, Helen S
  • Szpara, Moriah L
  • Lee, Angus Y
  • Cox, Jeffery S
  • Vance, Russell E
  • et al.
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.

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