1887

Abstract

To evade innate immunity, many viruses express interferon-antagonists that target STATs, critical mediators of immune signalling. Virus-STAT interfaces may provide new therapeutic targets but progress is hindered by a lack of direct structural data, owing to poor tractability of antagonists/full-length STATs for structural/biophysical approaches. By applying cross-saturation transfer NMR, we report the first direct structural analysis of binding of full-length STAT1 to an interferon-antagonist of a human pathogenic virus, the first such study of the virus-host interface. Analysis using mutation of the interface, biophysical characterization, immune signalling/protein-protein interaction assays including PCA, reverse genetics and animal infection demonstrated the significance of this interface in immune signaling suppression, and in disease caused by a pathogenic field-strain lyssavirus. Importantly, NMR/mutagenesis also revealed that the interface comprises multiple surfaces/domains in both the viral and cellular partners, indicating that antagonism involves extensive interactions consistent with a multifaceted inhibitory mechanism, distinct from ‘simple’ mechanisms such as tethering. Furthermore, by elucidating the spatial relationship of interactions critical to immune evasion and replication, the data provide insight into how ostensibly simple viruses can regulate these central functions via a single multifunctional protein. These data provide novel insights into fundamental viral biology, and potential exploitation of these mechanisms as new targets for antivirals and vaccine development. The study also demonstrates the power of biophysical/NMR approaches to elucidate the atomic interface of full-length STATs with regulatory proteins, providing a framework for studies to reveal immune evasion mechanisms of other pathogens in their full complexity.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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/content/journal/acmi/10.1099/acmi.ac2019.po0020
2019-04-08
2024-10-10
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