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

Abstract

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.

Inhibition of Histone H3 Lysine-27 Demethylase Activity Relieves Rheumatoid Arthritis Symptoms via Repression of IL6 Transcription in Macrophages

“…Nuclear extracts from BMDMs were prepared by high salt extraction ( 36 ). Electrophoretic Mobility Shift Assays (EMSA) were conducted by using EMSA/Gel shift kit (Beyotime) with the standard method as described previously ( 38 ). The NFκB consensus oligo sequence is 5′-AGT TGA GGG GAC TTT CCC AGG C-3′ and 5′- CGG ACC CTT TCA GGG GAG TTG A -3′.…”

Repurposing Multiple-Molecule Drugs for COVID-19-Associated Acute Respiratory Distress Syndrome and Non-Viral Acute Respiratory Distress Syndrome via a Systems Biology Approach and a DNN-DTI Model Based on Five Drug Design Specifications

“…TRAF6 could promote proinflammatory cytokines expression by activating downstream pathways of TAK1 and NFκB as aforementioned. TF STAT2, phosphorylated by TBK1, can promote innate immune response by activating its target gene IFNA1 [ 64 ]. However, ORF7a of SARS-CoV-2 has been found to interact with STAT2 as well.…”

Human Disease Phenotypes Associated with Loss and Gain of Function Mutations in STAT2: Viral Susceptibility and Type I Interferonopathy

“…Mutagenesis studies have identified that phosphorylation of additional residues (S287 [24], T387 [25], S734 [26]) on STAT2 negatively regulates its transcriptional activity. STAT2 T387 is constitutively phosphorylated, negatively regulating ISGF3 binding to DNA; constitutive phosphorylation at T403 maintains STAT2 dimerization with STAT1 [27]. By contrast, IFN-mediated acetylation of STAT2 K390 promotes transcription [28] (Fig.…”