Séminaire IBS : Viral strategies for immune evasion targeting the JAK-STAT pathway

Par Prof. Toyoyuki Ose, Hokkaido University, Sapporo, Japan

The capacity of viruses to target and inhibit immune signaling by the principal antiviral cytokines, interferons (IFNs), is critical to the outcomes of infection and disease, and is mediated by viral IFN-antagonist proteins. We have been working on viral IFN-antagonists from the order Mononegavirales such as genus Lyssavirus (e.g., rabies virus) and Morbillivirus (e.g., measles virus) that counteract the JAK-STAT system. STAT family members mediate signaling in the JAK–STAT pathway and are activated by phosphorylation at a conserved tyrosine residue, resulting in dimerization through reciprocal interactions between the phosphotyrosine and a SH2 domain.
Tyrosine-phosphorylated STAT (pY-STAT) then translocates to the nucleus to induce the expression of genes encoding antiviral proteins. Although the active and functional forms of STATs are conventionally considered to be dimers, STATs can undergo higher-order oligomerization, which is implicated in regulating transcriptional activity.

We presented the cryo-EM structures of the tetrameric form of intact pY-STAT1 in complex with DNA or the P protein of rabies viruses ^1,2. We explained the molecular architecture of the interactions by which P protein selectively antagonizes phosphorylated, activated STAT1. This novel binding mode explains previously undefined mechanisms by which P protein inhibits importin binding, DNA binding, and the conformational transition of activated STAT1 into its DNA-binding form, thus efficiently shutting down antiviral signaling. We also clarified that the C-terminal domain of the V protein from measles virus selectively binds to the core-region of STAT2 but not STAT1³. We were able to monitor that binding of V and IRF9 to STAT2-core is competitive ; V disrupts a preformed STAT2–IRF9 interaction, suggesting a new mechanism by which V can prevent type I IFN signaling by preventing STAT1–STAT2–IRF9 (the ISGF3 complex) formation^3,4. Taken together, our findings substantially advance molecular understanding of viral evasion of antiviral immunity, with high resolution molecular insights having the potential to inform novel intervention strategies for a lethal viral disease.

1. Rabies virus antagonizes interferon signaling by targeting phosphorylated STAT1 tetramers. bioRxiv 2026.07.29.741124 (2026) doi:10.64898/2026.07.29.741124.
2. Structural analysis reveals how tetrameric tyrosine-phosphorylated STAT1 is targeted by the rabies virus P-protein. Sci. Signal. 18, eads2210 (2025).
3. The Measles Virus V Protein Binding Site to STAT2 Overlaps That of IRF9. J. Virol. 94, e01169-20 (2020).
4. Solution structure of the C-terminal domain of the measles virus V protein in its free form and mechanistic analysis of STAT2 targeting. J. Virol. 99, e00739-25 (2025).

Hôte : Dr Jan Kadlec (IBS/EPIGEN)