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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

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258882/
https://www.ncbi.nlm.nih.gov/pubmed/35793327
http://dx.doi.org/10.1371/journal.ppat.1010645
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author 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
author_facet 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
author_sort Wang, Chenxi
collection PubMed
description 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 phospho-resistant mutation in the M1 protein to avoid viral protein degradation by host factors, which is advantageous in terms of replication in mammalian hosts.
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spelling pubmed-92588822022-07-07 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 PLoS Pathog Research Article 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 phospho-resistant mutation in the M1 protein to avoid viral protein degradation by host factors, which is advantageous in terms of replication in mammalian hosts. Public Library of Science 2022-07-06 /pmc/articles/PMC9258882/ /pubmed/35793327 http://dx.doi.org/10.1371/journal.ppat.1010645 Text en © 2022 Wang et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
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
title Enhanced stability of M1 protein mediated by a phospho-resistant mutation promotes the replication of prevailing avian influenza virus in mammals
title_full Enhanced stability of M1 protein mediated by a phospho-resistant mutation promotes the replication of prevailing avian influenza virus in mammals
title_fullStr Enhanced stability of M1 protein mediated by a phospho-resistant mutation promotes the replication of prevailing avian influenza virus in mammals
title_full_unstemmed Enhanced stability of M1 protein mediated by a phospho-resistant mutation promotes the replication of prevailing avian influenza virus in mammals
title_short Enhanced stability of M1 protein mediated by a phospho-resistant mutation promotes the replication of prevailing avian influenza virus in mammals
title_sort enhanced stability of m1 protein mediated by a phospho-resistant mutation promotes the replication of prevailing avian influenza virus in mammals
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258882/
https://www.ncbi.nlm.nih.gov/pubmed/35793327
http://dx.doi.org/10.1371/journal.ppat.1010645
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