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bioRxiv · 10.1101/2021.07.17.452491

A strategy to suppress STAT1 signalling conserved in pathogenic poxviruses and paramyxoviruses

Talbot-Cooper, C.·Pantelejevs, T.·Shannon, J. P.·Cherry, C. R.·Au, M. T.·Hyvönen, M.·Hickman, H. D.·Smith, G. L.
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Abstract

The induction of interferon-stimulated genes by signal transducer and activator of transcription (STAT) proteins, is a critical host defence to fight virus infections. Here, a highly expressed poxvirus protein 018 is shown to inhibit IFN-induced signalling by binding the SH2 domain of STAT1 to prevent STAT1 association with an activated IFN receptor. Despite the presence of additional inhibitors of IFN-induced signalling, a poxvirus lacking 018 was attenuated in mice. The 2.0 [A] crystal structure of the 018:STAT1 complex reveals a mechanism for a high-affinity, pTyr-independent mode of binding to an SH2 domain. Furthermore, the STAT1 binding motif of 018 shows sequence similarity to the STAT1-binding proteins from Nipah virus, which like 018, block the association of STAT1 with an IFN receptor. Taken together, these results provide detailed mechanistic insight into a potent mode of STAT1 antagonism, found to exist in genetically diverse virus families.

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Talbot-Cooper, C., Pantelejevs, T., Shannon, J. P., Cherry, C. R., Au, M. T., Hyvönen, M., Hickman, H. D., Smith, G. L.. 2021-07-17. A strategy to suppress STAT1 signalling conserved in pathogenic poxviruses and paramyxoviruses. https://doi.org/10.1101/2021.07.17.452491

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