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Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response
The Hippo signaling pathway, which is historically considered as a dominator of organ development and homeostasis has recently been implicated as an immune regulator. However, its role in host defense against influenza A virus (IAV) has not been widely investigated. Here, we found that IAV could act...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122210/ https://www.ncbi.nlm.nih.gov/pubmed/35503798 http://dx.doi.org/10.1371/journal.ppat.1010505 |
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author | Zhang, Qiong Zhang, Xujun Lei, Xiaobo Wang, Hai Jiang, Jingjing Wang, Yuchong Bi, Kefan Diao, Hongyan |
author_facet | Zhang, Qiong Zhang, Xujun Lei, Xiaobo Wang, Hai Jiang, Jingjing Wang, Yuchong Bi, Kefan Diao, Hongyan |
author_sort | Zhang, Qiong |
collection | PubMed |
description | The Hippo signaling pathway, which is historically considered as a dominator of organ development and homeostasis has recently been implicated as an immune regulator. However, its role in host defense against influenza A virus (IAV) has not been widely investigated. Here, we found that IAV could activate the Hippo effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) through physical binding of the IAV non-structural protein 1 (NS1) with C-terminal domain of YAP/TAZ, facilitating their nuclear location. Meanwhile, YAP/TAZ downregulated the expression of pro-inflammatory and anti-viral cytokines against IAV infection, therefore benefiting virus replication and host cell apoptosis. A mouse model of IAV infection further demonstrated Yap deficiency protected mice against IAV infection, relieving lung injury. Mechanistically, YAP/TAZ blocked anti-viral innate immune signaling via downregulation of Toll-like receptor 3 (TLR3) expression. YAP directly bound to the putative TEADs binding site on the promoter region of TLR3. The elimination of acetylated histone H3 occupancy in the TLR3 promoter resulted in its transcriptional silence. Moreover, treatment of Trichostatin A, a histone deacetylases (HDACs) inhibitor or disruption of HDAC4/6 reversed the inhibition of TLR3 expression by YAP/TAZ, suggesting HDAC4/6 mediated the suppression function of YAP/TAZ. Taken together, we uncovered a novel immunomodulatory mechanism employed by IAV, where YAP/TAZ antagonize TLR3-mediated innate immunity. |
format | Online Article Text |
id | pubmed-9122210 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-91222102022-05-21 Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response Zhang, Qiong Zhang, Xujun Lei, Xiaobo Wang, Hai Jiang, Jingjing Wang, Yuchong Bi, Kefan Diao, Hongyan PLoS Pathog Research Article The Hippo signaling pathway, which is historically considered as a dominator of organ development and homeostasis has recently been implicated as an immune regulator. However, its role in host defense against influenza A virus (IAV) has not been widely investigated. Here, we found that IAV could activate the Hippo effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) through physical binding of the IAV non-structural protein 1 (NS1) with C-terminal domain of YAP/TAZ, facilitating their nuclear location. Meanwhile, YAP/TAZ downregulated the expression of pro-inflammatory and anti-viral cytokines against IAV infection, therefore benefiting virus replication and host cell apoptosis. A mouse model of IAV infection further demonstrated Yap deficiency protected mice against IAV infection, relieving lung injury. Mechanistically, YAP/TAZ blocked anti-viral innate immune signaling via downregulation of Toll-like receptor 3 (TLR3) expression. YAP directly bound to the putative TEADs binding site on the promoter region of TLR3. The elimination of acetylated histone H3 occupancy in the TLR3 promoter resulted in its transcriptional silence. Moreover, treatment of Trichostatin A, a histone deacetylases (HDACs) inhibitor or disruption of HDAC4/6 reversed the inhibition of TLR3 expression by YAP/TAZ, suggesting HDAC4/6 mediated the suppression function of YAP/TAZ. Taken together, we uncovered a novel immunomodulatory mechanism employed by IAV, where YAP/TAZ antagonize TLR3-mediated innate immunity. Public Library of Science 2022-05-03 /pmc/articles/PMC9122210/ /pubmed/35503798 http://dx.doi.org/10.1371/journal.ppat.1010505 Text en © 2022 Zhang 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 Zhang, Qiong Zhang, Xujun Lei, Xiaobo Wang, Hai Jiang, Jingjing Wang, Yuchong Bi, Kefan Diao, Hongyan Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response |
title | Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response |
title_full | Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response |
title_fullStr | Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response |
title_full_unstemmed | Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response |
title_short | Influenza A virus NS1 protein hijacks YAP/TAZ to suppress TLR3-mediated innate immune response |
title_sort | influenza a virus ns1 protein hijacks yap/taz to suppress tlr3-mediated innate immune response |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9122210/ https://www.ncbi.nlm.nih.gov/pubmed/35503798 http://dx.doi.org/10.1371/journal.ppat.1010505 |
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