期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-08524-3
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资金
- Chinese National Program on Key Basic Research Project [2017YFA0505900]
- Chinese National Program on Key Basic Research Project (973 Programs) [2012CB578100, 2011CB505000]
- National Natural Science Foundation of China [31730025, 31670901, 91542111, 81330069, 81800004]
- National Key Research and Development Program of China [2016YFC1305103]
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning [TP2016007]
- Shanghai Pujiang Program [16PJ1401400]
- Outstanding Youth Training Program of Shanghai Municipal Commission of Health and Family Planning [2017YQ012]
- Fundamental Research Funds for the Central Universities [22120180024]
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.
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