A virus-induced conformational switch of STAT1-STAT2 dimers boosts antiviral defenses

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-epsilon, 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.

Automated summary

Type I interferons (IFN-I) play a crucial role in protecting against viral infections, with STAT2 being a key component in driving gene expression in response to IFN-I. The phosphorylation of STAT2 at T404 acts as a critical conformational switch, disrupting an inactive STAT1-STAT2 dimer and enhancing the antiviral defense response to IFN-I. Additionally, virus infection-induced activation of IKK-epsilon can directly phosphorylate T404, further facilitating the antiviral defense mechanism.