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 beta 2 inhibits the virus-induced expression of pro-inflammatory cytokines by interacting with and inhibiting transforming growth factor-beta-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 proinflammatory cytokines. Moreover, PLC beta 2-deficient mice exhibit increased expression of proinflammatory cytokines and a higher frequency of death in response to virus infection, while the PLC beta 2 activator, m-3M3FBS, protects mice from severe Coxsackie virus A 16 (CVA16) infection. Thus, our findings suggest that PLCI beta 2 negatively regulates virus-induced pro-inflammatory responses by inhibiting phosphoinositide-mediated activation of TAK1.
[1]Tongji Univ, Shanghai Pulm Hosp, Sch Med, Shanghai 200433, Peoples R China;
[2]Fudan Univ, Dept Immunol, Sch Basic Med Sci, Shanghai 200032, Peoples R China;
[3]Fudan Univ, Shanghai Publ Hlth Clin Ctr, Key Lab Med Mol Virol MOE MOH, Shanghai 200032, Peoples R China;
[4]Shanghai Jiao Tong Univ, Sch Pharm, Shanghai 200240, Peoples R China;
[5]Inst Pasteur Shanghai, Shanghai 200031, Peoples R China;
[6]Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, Shanghai 200000, Peoples R China;
[7]Fudan Univ, Dept Clin Immunol, Childrens Hosp, Shanghai 201102, Peoples R China;
[8]Yale Sch Med, Dept Pharmacol, New Haven, CT 06520 USA;
[9]Fudan Univ, Dept Chem, Shanghai 200032, Peoples R China;
[10]Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China
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