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Enhanced stability of M1 protein mediated by a phospho-resistant mutation promotes the replication of prevailing avian influenza virus in mammals

Wang, Chenxi; Qu, Runkang; Zong, Yanan; Qin, Chao; Liu, Litao; Gao, Xiaoyi; Sun, Honglei; Sun, Yipeng; Chang, Kin Chow; Zhang, Rui; Liu, Jinhua; Pu, Juan

Enhanced stability of M1 protein mediated by a phospho-resistant mutation promotes the replication of prevailing avian influenza virus in mammals Thumbnail


Authors

Chenxi Wang

Runkang Qu

Yanan Zong

Chao Qin

Litao Liu

Xiaoyi Gao

Honglei Sun

Yipeng Sun

KIN-CHOW CHANG KIN-CHOW.CHANG@NOTTINGHAM.AC.UK
Professor of Veterinary Molecular Medicine

Rui Zhang

Jinhua Liu

Juan Pu



Contributors

Anice C. Lowen
Editor

Abstract

Avian influenza virus (AIV) can evolve multiple strategies to combat host antiviral defenses and establish efficient infectivity in mammals, including humans. H9N2 AIV and its reassortants (such as H5N6 and H7N9 viruses) pose an increasing threat to human health; however, the mechanisms involved in their increased virulence remain poorly understood. We previously reported that the M1 mutation T37A has become predominant among chicken H9N2 isolates in China. Here, we report that, since 2010, this mutation has also been found in the majority of human isolates of H9N2 AIV and its emerging reassortants. The T37A mutation of M1 protein enhances the replication of H9N2 AIVs in mice and in human cells. Interestingly, having A37 instead of T37 increases the M1 protein stability and resistance to proteasomal degradation. Moreover, T37 of the H9N2 M1 protein is phosphorylated by protein kinase G (PKG), and this phosphorylation induces the rapid degradation of M1 and reduces viral replication. Similar effects are also observed in the novel H5N6 virus. Additionally, ubiquitination at K187 contributes to M1-37T degradation and decreased replication of the virus harboring T37 in the M1 protein. The prevailing AIVs thereby evolve a phosphoresistant mutation in the M1 protein to avoid viral protein degradation by host factors, which is advantageous in terms of replication in mammalian hosts.

Citation

Wang, C., Qu, R., Zong, Y., Qin, C., Liu, L., Gao, X., …Pu, J. (2022). Enhanced stability of M1 protein mediated by a phospho-resistant mutation promotes the replication of prevailing avian influenza virus in mammals. PLoS Pathogens, 18(7), Article e1010645. https://doi.org/10.1371/journal.ppat.1010645

Journal Article Type Article
Acceptance Date Jun 3, 2022
Online Publication Date Jul 6, 2022
Publication Date Jul 1, 2022
Deposit Date Jul 11, 2022
Publicly Available Date Mar 29, 2024
Journal PLoS Pathogens
Print ISSN 1553-7366
Electronic ISSN 1553-7374
Publisher Public Library of Science (PLoS)
Peer Reviewed Peer Reviewed
Volume 18
Issue 7
Article Number e1010645
DOI https://doi.org/10.1371/journal.ppat.1010645
Keywords Virology; Genetics; Molecular Biology; Immunology; Microbiology; Parasitology
Public URL https://nottingham-repository.worktribe.com/output/8947622
Publisher URL https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1010645

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