Type I interferons (IFN-I) protect us from viral infections. Signal transducer and activator of transcription 2 (STAT2) is a key component of interferon-stimulated gene factor 3 (ISGF3), which drives gene expression in response to IFN-I. Using electron microscopy, we found that, in naive cells, U-STAT2, lacking the activating tyrosine phosphorylation, forms a heterodimer with U-STAT1 in an inactive, anti-parallel conformation. A novel phosphorylation of STAT2 on T404 promotes IFN-I signaling by disrupting the U-STAT1-U-STAT2 dimer, facilitating the tyrosine phosphorylation of STATs 1 and 2 and enhancing the DNA-binding ability of ISGF3. IKK-ε, activated by virus infection, phosphorylates T404 directly. Mice with a T-A mutation at the corresponding residue (T403) are highly susceptible to virus infections. We conclude that T404 phosphorylation drives a critical conformational switch that, by boosting the response to IFN-I in infected cells, enables a swift and efficient antiviral defense.

I 型干扰素 (IFN-I) 保护我们免受病毒感染。信号转导和转录激活因子 2 (STAT2) 是干扰素刺激基因因子 3 (ISGF3) 的关键组成部分，它驱动基因表达以响应 IFN-I。使用电子显微镜，我们发现，在幼稚细胞中，缺乏激活酪氨酸磷酸化的 U-STAT2 与 U-STAT1 形成异二聚体，处于非活性、反平行构象。T404 上 STAT2 的新磷酸化通过破坏 U-STAT1-U-STAT2 二聚体促进 IFN-I 信号传导，促进 STATs 1 和 2 的酪氨酸磷酸化并增强 ISGF3 的 DNA 结合能力。IKK-ε 被病毒感染激活，直接磷酸化 T404。在相应残基 (T403) 处具有 TA 突变的小鼠对病毒感染高度敏感。