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

Lin Wang, Yilong Zhou, Zijuan Chen, Lei Sun, Juehui Wu, Haohao Li, Feng Liu, Fei Wang, Chunfu Yang, Juhao Yang, Qibin Leng, Qingli Zhang, Ajing Xu, Lisong Shen, Jinqiao Sun, Dianqing Wu, Caiyun Fang, Haojie Lu (), Dapeng Yan () and Baoxue Ge ()
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Lin Wang: Tongji University School of Medicine
Yilong Zhou: Tongji University School of Medicine
Zijuan Chen: Fudan University
Lei Sun: Shanghai Jiao Tong University
Juehui Wu: Tongji University School of Medicine
Haohao Li: Tongji University School of Medicine
Feng Liu: Tongji University School of Medicine
Fei Wang: Tongji University School of Medicine
Chunfu Yang: Institut Pasteur of Shanghai
Juhao Yang: Institut Pasteur of Shanghai
Qibin Leng: Institut Pasteur of Shanghai
Qingli Zhang: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Ajing Xu: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Lisong Shen: Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
Jinqiao Sun: Children’s Hospital of Fudan University
Dianqing Wu: Yale School of Medicine
Caiyun Fang: Fudan University
Haojie Lu: Fudan University
Dapeng Yan: Fudan University
Baoxue Ge: Tongji University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-08524-3

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