PLC beta 2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
PLC beta 2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
复制标题
PLCβ2 通过抑制磷酸肌醇介导的 TAK1 激活负调节病毒感染的炎症反应
DOI：
10.1038/s41467-019-08524-3
复制
发表时间：
2019
影响因子：
16.6
通讯作者：
Ge Baoxue
中科院分区：
文献类型：
--
作者：
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
由严重病毒感染引起的促炎细胞因子的过度或不受控制的释放通常导致宿主组织损伤甚至死亡。磷脂酶C（PLC）降解磷脂酰肌醇-4，5-二磷酸（PI（4，5）P2）脂质并调节多种细胞事件。在此，我们报道PLC β 2通过与转化生长因子-β-激活激酶1（TAK1）相互作用并抑制其活化来抑制病毒诱导的促炎细胞因子的表达。在机制上，PI（4，5）P2脂质在W241和N245处直接与TAK1相互作用，并促进其活化。破坏PI（4，5）P2的结合亲和力或TAK1上PIP2结合位点的突变可消除其活化和随后的促炎细胞因子的产生。此外，PLC β 2缺陷型小鼠表现出促炎细胞因子表达增加和对病毒感染应答的较高死亡频率，而PLC β 2激活剂m-3M3 FBS保护小鼠免受严重的科萨基病毒A 16（CVA 16）感染。因此，我们的研究结果表明，PLC β 2通过抑制磷酸肌醇介导的TAK1活化来负性调节病毒诱导的促炎反应。
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.