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Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis

Viruses induce double-stranded RNA (dsRNA) in the host cells. The mammalian system has developed dsRNA-dependent recognition receptors such as RLRs that recognize the long stretches of dsRNA as PAMPs to activate interferon-mediated antiviral pathways and apoptosis in severe infection. Here we report...

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Autores principales: Wang, Wei, Wang, Wei-Hua, Azadzoi, Kazem M., Su, Ning, Dai, Peng, Sun, Jianbin, Wang, Qin, Liang, Ping, Zhang, Wentao, Lei, Xiaoying, Yan, Zhen, Yang, Jing-Hua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776105/
https://www.ncbi.nlm.nih.gov/pubmed/26935990
http://dx.doi.org/10.1038/srep22550
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author Wang, Wei
Wang, Wei-Hua
Azadzoi, Kazem M.
Su, Ning
Dai, Peng
Sun, Jianbin
Wang, Qin
Liang, Ping
Zhang, Wentao
Lei, Xiaoying
Yan, Zhen
Yang, Jing-Hua
author_facet Wang, Wei
Wang, Wei-Hua
Azadzoi, Kazem M.
Su, Ning
Dai, Peng
Sun, Jianbin
Wang, Qin
Liang, Ping
Zhang, Wentao
Lei, Xiaoying
Yan, Zhen
Yang, Jing-Hua
author_sort Wang, Wei
collection PubMed
description Viruses induce double-stranded RNA (dsRNA) in the host cells. The mammalian system has developed dsRNA-dependent recognition receptors such as RLRs that recognize the long stretches of dsRNA as PAMPs to activate interferon-mediated antiviral pathways and apoptosis in severe infection. Here we report an efficient antiviral immune response through dsRNA-dependent RLR receptor-mediated necroptosis against infections from different classes of viruses. We demonstrated that virus-infected A549 cells were efficiently killed in the presence of a chimeric RLR receptor, dsCARE. It measurably suppressed the interferon antiviral pathway but promoted IL-1β production. Canonical cell death analysis by morphologic assessment, phosphatidylserine exposure, caspase cleavage and chemical inhibition excluded the involvement of apoptosis and consistently suggested RLR receptor-mediated necroptosis as the underlying mechanism of infected cell death. The necroptotic pathway was augmented by the formation of RIP1-RIP3 necrosome, recruitment of MLKL protein and the activation of cathepsin D. Contributing roles of RIP1 and RIP3 were confirmed by gene knockdown. Furthermore, the necroptosis inhibitor necrostatin-1 but not the pan-caspase inhibitor zVAD impeded dsCARE-dependent infected cell death. Our data provides compelling evidence that the chimeric RLR receptor shifts the common interferon antiviral responses of infected cells to necroptosis and leads to rapid death of the virus-infected cells. This mechanism could be targeted as an efficient antiviral strategy.
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spelling pubmed-47761052016-03-09 Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis Wang, Wei Wang, Wei-Hua Azadzoi, Kazem M. Su, Ning Dai, Peng Sun, Jianbin Wang, Qin Liang, Ping Zhang, Wentao Lei, Xiaoying Yan, Zhen Yang, Jing-Hua Sci Rep Article Viruses induce double-stranded RNA (dsRNA) in the host cells. The mammalian system has developed dsRNA-dependent recognition receptors such as RLRs that recognize the long stretches of dsRNA as PAMPs to activate interferon-mediated antiviral pathways and apoptosis in severe infection. Here we report an efficient antiviral immune response through dsRNA-dependent RLR receptor-mediated necroptosis against infections from different classes of viruses. We demonstrated that virus-infected A549 cells were efficiently killed in the presence of a chimeric RLR receptor, dsCARE. It measurably suppressed the interferon antiviral pathway but promoted IL-1β production. Canonical cell death analysis by morphologic assessment, phosphatidylserine exposure, caspase cleavage and chemical inhibition excluded the involvement of apoptosis and consistently suggested RLR receptor-mediated necroptosis as the underlying mechanism of infected cell death. The necroptotic pathway was augmented by the formation of RIP1-RIP3 necrosome, recruitment of MLKL protein and the activation of cathepsin D. Contributing roles of RIP1 and RIP3 were confirmed by gene knockdown. Furthermore, the necroptosis inhibitor necrostatin-1 but not the pan-caspase inhibitor zVAD impeded dsCARE-dependent infected cell death. Our data provides compelling evidence that the chimeric RLR receptor shifts the common interferon antiviral responses of infected cells to necroptosis and leads to rapid death of the virus-infected cells. This mechanism could be targeted as an efficient antiviral strategy. Nature Publishing Group 2016-03-03 /pmc/articles/PMC4776105/ /pubmed/26935990 http://dx.doi.org/10.1038/srep22550 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Wang, Wei
Wang, Wei-Hua
Azadzoi, Kazem M.
Su, Ning
Dai, Peng
Sun, Jianbin
Wang, Qin
Liang, Ping
Zhang, Wentao
Lei, Xiaoying
Yan, Zhen
Yang, Jing-Hua
Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis
title Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis
title_full Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis
title_fullStr Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis
title_full_unstemmed Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis
title_short Activation of innate antiviral immune response via double-stranded RNA-dependent RLR receptor-mediated necroptosis
title_sort activation of innate antiviral immune response via double-stranded rna-dependent rlr receptor-mediated necroptosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4776105/
https://www.ncbi.nlm.nih.gov/pubmed/26935990
http://dx.doi.org/10.1038/srep22550
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