Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3
Apoptotic Caspases Suppress Type I Interferon Production via the Cleavage of cGAS, MAVS, and IRF3
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DOI：
10.1016/j.molcel.2019.02.013
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发表时间：
2019-04-04
期刊：
影响因子：
16
通讯作者：
Jiang, Zhengfan
中科院分区：
文献类型：
--
作者：
Ning, Xiaohan;Wang, Yutao;Jiang, Zhengfan
病毒感染通过模式识别受体介导的细胞因子产生、炎性小体激活和受感染细胞的凋亡触发宿主防御。已知炎性小体激活的半胱天冬酶切割环GMP-AMP合酶（cGAS）。在这里，我们发现凋亡半胱天冬酶在调节DNA和RNA病毒触发的宿主防御中起关键作用，其中激活的半胱天冬酶3切割cGAS，MAVS和IRF 3以防止细胞因子过度产生。Caspase-3是人类细胞中唯一需要的，而caspase-7仅在鼠细胞中参与抑制cGAS，反映了不同物种的不同调控机制。在dsDNA存在下，胱天蛋白酶介导的cGAS切割增强。使用替代的MAVS切割位点来确保该关键蛋白质的失活。在没有任何感染的情况下，在caspase-3缺陷细胞中检测到升高的I型IFN。Casp 3（-/-）小鼠对病毒感染和实验性自身免疫性脑脊髓炎的抵抗力持续增强。我们的研究结果表明，凋亡半胱天冬酶控制先天免疫和维持免疫稳态对病毒感染。
Viral infection triggers host defenses through pattern-recognition receptor-mediated cytokine production, inflammasome activation, and apoptosis of the infected cells. Inflammasome-activated caspases are known to cleave cyclic GMP-AMP synthase (cGAS). Here, we found that apoptotic caspases are critically involved in regulating both DNA and RNA virus-triggered host defenses, in which activated caspase-3 cleaved cGAS, MAVS, and IRF3 to prevent cytokine overproduction. Caspase-3 was exclusively required in human cells, whereas caspase-7 was involved only in murine cells to inactivate cGAS, reflecting distinct regulatory mechanisms in different species. Caspase-mediated cGAS cleavage was enhanced in the presence of dsDNA. Alternative MAVS cleavage sites were used to ensure the inactivation of this critical protein. Elevated type I IFNs were detected in caspase-3-deficient cells without any infection. Casp3(-/-) mice consistently showed increased resistance to viral infection and experimental autoimmune encephalomyelitis. Our results demonstrate that apoptotic caspases control innate immunity and maintain immune homeostasis against viral infection.