Structural Elucidation of Viral Antagonism of Innate Immunity at the STAT1 Interface

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Hossain, Md Alamgir | Larrous, Florence | Rawlinson, Stephen | Zhan, Jingyu | Sethi, Ashish | Ibrahim, Youssef | Aloi, Maria | Lieu, Kim | Mok, Yee-Foong | Griffin, Michael | Ito, Naoto | Ose, Toyoyuki | Bourhy, Hervé | Moseley, Gregory | Gooley, Paul

Edité par CCSD ; Elsevier Inc -

International audience. To evade immunity, many viruses express interferon antagonists that target STAT transcription factors as a major component of pathogenesis. Because of a lack of direct structural data, these interfaces are poorly understood. We report the structural analysis of full-length STAT1 binding to an interferon antagonist of a human pathogenic virus. The interface revealed by transferred cross-saturation NMR is complex, involving multiple regions in both the viral and cellular proteins. Molecular mapping analysis, combined with biophysical characterization and in vitro/in vivo functional assays, indicates that the interface is significant in disease caused by a pathogenic field-strain lyssavirus, with critical roles for contacts between the STAT1 coiled-coil/DNA-binding domains and specific regions within the viral protein. These data elucidate the potentially complex nature of IFN antagonist/STAT interactions, and the spatial relationship of protein interfaces that mediate immune evasion and replication, providing insight into how viruses can regulate these essential functions via single multifunctional proteins.

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