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PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1

Excessive or uncontrolled release of proinflammatory cytokines caused by severe viral infections often results in host tissue injury or even death. Phospholipase C (PLC)s degrade phosphatidylinositol-4, 5-bisphosphate (PI(4,5)P2) lipids and regulate multiple cellular events. Here, we report that PLC...

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Autores principales: Wang, Lin, Zhou, Yilong, Chen, Zijuan, Sun, Lei, Wu, Juehui, Li, Haohao, Liu, Feng, Wang, Fei, Yang, Chunfu, Yang, Juhao, Leng, Qibin, Zhang, Qingli, Xu, Ajing, Shen, Lisong, Sun, Jinqiao, Wu, Dianqing, Fang, Caiyun, Lu, Haojie, Yan, Dapeng, Ge, Baoxue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375925/
https://www.ncbi.nlm.nih.gov/pubmed/30765691
http://dx.doi.org/10.1038/s41467-019-08524-3
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author Wang, Lin
Zhou, Yilong
Chen, Zijuan
Sun, Lei
Wu, Juehui
Li, Haohao
Liu, Feng
Wang, Fei
Yang, Chunfu
Yang, Juhao
Leng, Qibin
Zhang, Qingli
Xu, Ajing
Shen, Lisong
Sun, Jinqiao
Wu, Dianqing
Fang, Caiyun
Lu, Haojie
Yan, Dapeng
Ge, Baoxue
author_facet Wang, Lin
Zhou, Yilong
Chen, Zijuan
Sun, Lei
Wu, Juehui
Li, Haohao
Liu, Feng
Wang, Fei
Yang, Chunfu
Yang, Juhao
Leng, Qibin
Zhang, Qingli
Xu, Ajing
Shen, Lisong
Sun, Jinqiao
Wu, Dianqing
Fang, Caiyun
Lu, Haojie
Yan, Dapeng
Ge, Baoxue
author_sort Wang, Lin
collection PubMed
description Excessive or uncontrolled release of proinflammatory cytokines caused by severe viral infections often results in host tissue injury or even death. Phospholipase C (PLC)s degrade phosphatidylinositol-4, 5-bisphosphate (PI(4,5)P2) lipids and regulate multiple cellular events. Here, we report that PLCβ2 inhibits the virus-induced expression of pro-inflammatory cytokines by interacting with and inhibiting transforming growth factor-β-activated kinase 1 (TAK1) activation. Mechanistically, PI(4,5)P2 lipids directly interact with TAK1 at W241 and N245, and promote its activation. Impairing of PI(4,5)P2’s binding affinity or mutation of PIP2-binding sites on TAK1 abolish its activation and the subsequent production of pro-inflammatory cytokines. Moreover, PLCβ2-deficient mice exhibit increased expression of proinflammatory cytokines and a higher frequency of death in response to virus infection, while the PLCβ2 activator, m-3M3FBS, protects mice from severe Coxsackie virus A 16 (CVA16) infection. Thus, our findings suggest that PLCβ2 negatively regulates virus-induced pro-inflammatory responses by inhibiting phosphoinositide-mediated activation of TAK1.
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spelling pubmed-63759252019-02-19 PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1 Wang, Lin Zhou, Yilong Chen, Zijuan Sun, Lei Wu, Juehui Li, Haohao Liu, Feng Wang, Fei Yang, Chunfu Yang, Juhao Leng, Qibin Zhang, Qingli Xu, Ajing Shen, Lisong Sun, Jinqiao Wu, Dianqing Fang, Caiyun Lu, Haojie Yan, Dapeng Ge, Baoxue Nat Commun Article Excessive or uncontrolled release of proinflammatory cytokines caused by severe viral infections often results in host tissue injury or even death. Phospholipase C (PLC)s degrade phosphatidylinositol-4, 5-bisphosphate (PI(4,5)P2) lipids and regulate multiple cellular events. Here, we report that PLCβ2 inhibits the virus-induced expression of pro-inflammatory cytokines by interacting with and inhibiting transforming growth factor-β-activated kinase 1 (TAK1) activation. Mechanistically, PI(4,5)P2 lipids directly interact with TAK1 at W241 and N245, and promote its activation. Impairing of PI(4,5)P2’s binding affinity or mutation of PIP2-binding sites on TAK1 abolish its activation and the subsequent production of pro-inflammatory cytokines. Moreover, PLCβ2-deficient mice exhibit increased expression of proinflammatory cytokines and a higher frequency of death in response to virus infection, while the PLCβ2 activator, m-3M3FBS, protects mice from severe Coxsackie virus A 16 (CVA16) infection. Thus, our findings suggest that PLCβ2 negatively regulates virus-induced pro-inflammatory responses by inhibiting phosphoinositide-mediated activation of TAK1. Nature Publishing Group UK 2019-02-14 /pmc/articles/PMC6375925/ /pubmed/30765691 http://dx.doi.org/10.1038/s41467-019-08524-3 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wang, Lin
Zhou, Yilong
Chen, Zijuan
Sun, Lei
Wu, Juehui
Li, Haohao
Liu, Feng
Wang, Fei
Yang, Chunfu
Yang, Juhao
Leng, Qibin
Zhang, Qingli
Xu, Ajing
Shen, Lisong
Sun, Jinqiao
Wu, Dianqing
Fang, Caiyun
Lu, Haojie
Yan, Dapeng
Ge, Baoxue
PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
title PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
title_full PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
title_fullStr PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
title_full_unstemmed PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
title_short PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
title_sort plcβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of tak1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375925/
https://www.ncbi.nlm.nih.gov/pubmed/30765691
http://dx.doi.org/10.1038/s41467-019-08524-3
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