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.

干扰素基因刺激物 (STING) 通路在识别 DNA 后启动有效的免疫反应。为了启动信号传导，STING 的 C 末端尾 (CTT) 中的丝氨酸 365 (S365) 被磷酸化，导致 I 型干扰素 (IFN) 的诱导。此外，自噬等进化保守反应也发生在 STING 的下游，但它们在体内感染中的相对重要性仍不清楚。在这里，我们报告在 STING 中携带丝氨酸 365 到丙氨酸 (S365A) 突变的小鼠出乎意料地对单纯疱疹病毒 (HSV)-1 具有抗性，尽管缺乏 STING 诱导的 I 型 IFN 反应。相比之下，在缺乏 STING CTT 的小鼠中，对 HSV-1 的抗性被消除，这表明 STING CTT 引发了对 HSV-1 的保护性反应，与 I 型干扰素无关。有趣的是，我们发现 STING 诱导的自噬是一个依赖于 CTT 和 TBK1 但不依赖于 IRF3 的过程，在 STING S365A 小鼠中是保守的。因此，STING 的干扰素非依赖性功能在体内介导 STING 依赖性抗病毒反应。