The influenza virus PB2 protein evades antiviral innate immunity by inhibiting JAK1/STAT signalling

Hui Yang, Yurui Dong, Ying Bian, Nuo Xu, Yuwei Wu, Fan Yang, Yinping Du, Tao Qin, Sujuan Chen (), Daxin Peng () and Xiufan Liu
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Hui Yang: Yangzhou University
Yurui Dong: Yangzhou University
Ying Bian: Yangzhou University
Nuo Xu: Yangzhou University
Yuwei Wu: Yangzhou University
Fan Yang: Yangzhou University
Yinping Du: Yangzhou University
Tao Qin: Yangzhou University
Sujuan Chen: Yangzhou University
Daxin Peng: Yangzhou University
Xiufan Liu: Yangzhou University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Influenza A virus (IAV) polymerase protein PB2 has been shown to partially inhibit the host immune response by blocking the induction of interferons (IFNs). However, the IAV PB2 protein that regulates the downstream signaling pathway of IFNs is not well characterized. Here, we report that IAV PB2 protein reduces cellular sensitivity to IFNs, suppressing the activation of STAT1/STAT2 and ISGs. Furthermore, IAV PB2 protein targets mammalian JAK1 at lysine 859 and 860 for ubiquitination and degradation. Notably, the H5 subtype of highly pathogenic avian influenza virus with I283M/K526R mutations on PB2 increases the ability to degrade mammalian JAK1 and exhibits higher replicate efficiency in mammalian (but not avian) cells and mouse lung tissues, and causes greater mortality in infected mice. Altogether, these data describe a negative regulatory mechanism involving PB2-JAK1 and provide insights into an evasion strategy from host antiviral immunity employed by IAV.

Date: 2022
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DOI: 10.1038/s41467-022-33909-2

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