Inflammasome Activation Triggers Caspase-1-Mediated Cleavage of cGAS to Regulate Responses to DNA Virus Infection
Inflammasome Activation Triggers Caspase-1-Mediated Cleavage of cGAS to Regulate Responses to DNA Virus Infection
复制标题
炎症小体激活触发 Caspase-1 介导的 cGAS 裂解，调节对 DNA 病毒感染的反应
DOI：
10.1016/j.immuni.2017.02.011
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发表时间：
2017-03-21
期刊：
影响因子：
32.4
通讯作者：
Jiang, Zhengfan
中科院分区：
文献类型：
--
作者：
Wang, Yutao;Ning, Xiaohan;Jiang, Zhengfan
病毒感染触发宿主先天免疫应答，其导致包括I型干扰素（IFN）在内的各种细胞因子的产生、炎性小体的活化和感染细胞的程序性细胞死亡。严格控制炎性细胞因子的产生对于触发有效的免疫应答是至关重要的，该免疫应答可以解决感染而不引起宿主病理学。在检查Asc（-/-）和Casp 1（-/-）巨噬细胞的炎症反应时，我们发现这些分子的缺陷导致DNA病毒感染时IFN产生增加，但不是RNA病毒攻击。对潜在机制的研究表明，在典型和非典型炎性小体活化后，胱天蛋白酶-1与环GMP-AMP（cGAMP）合酶（cGAS）相互作用，将其裂解并抑制cGASSTING介导的IFN产生。炎性小体信号传导的缺陷增强了宿主对DNA病毒的体外和体内抵抗力，并且这种调节作用延伸到其他炎性半胱天冬酶。因此，炎性小体激活抑制cGAS依赖性信号传导，表明细胞内DNA传感途径之间的交叉调节。
Viral infection triggers host innate immune responses that result in the production of various cytokines including type I interferons (IFN), activation of inflammasomes, and programmed cell death of the infected cells. Tight control of inflammatory cytokine production is crucial for the triggering of an effective immune response that can resolve the infection without causing host pathology. In examining the inflammatory response of Asc(-/-) and Casp1(-/-) macrophages, we found that deficiency in these molecules resulted in increased IFN production upon DNA virus infection, but not RNA virus challenge. Investigation of the underlying mechanism revealed that upon canonical and non-canonical inflammasome activation, caspase- 1 interacted with cyclic GMP-AMP (cGAMP) synthase (cGAS), cleaving it and dampening cGASSTING- mediated IFN production. Deficiency in inflammasome signaling enhanced host resistance to DNA virus in vitro and in vivo, and this regulatory role extended to other inflammatory caspases. Thus, inflammasome activation dampens cGAS-dependent signaling, suggesting cross-regulation between intracellular DNA-sensing pathways.