Recognition of pathogen-associated molecular patterns and danger-associated molecular patterns by host cells is an important step in innate immune activation. The DNA sensor cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) binds to DNA and produces cGAMP, which in turn binds to stimulator of interferon genes (STING) to activate IFN-I. Here we show that cGAMP has a noncanonical function in inflammasome activation in human and mouse cells. Inflammasome activation requires two signals, both of which are activated by cGAMP. cGAMP alone enhances expression of inflammasome components through IFN-I, providing the priming signal. Additionally, when combined with a priming signal, cGAMP activates the inflammasome through an AIM2, NLRP3, ASC, and caspase-1 dependent process. These two cGAMP-mediated functions, priming and activation, have differential requirements for STING. Temporally, cGAMP induction of IFN-I precedes inflammasome activation, which then occurs when IFN-I is waning. In mice, cGAS/cGAMP amplify both inflammasome and IFN-I to control murine cytomegalovirus. Thus, cGAMP activates the inflammasome in addition to IFN-I, and activation of both is needed to control infection by a DNA virus.

宿主细胞识别病原体相关分子模式和危险相关分子模式是先天免疫激活的重要步骤。DNA传感器环状鸟苷一磷酸一腺苷单磷酸（cGAMP）合酶（cGAS）与DNA结合并产生cGAMP，后者又与干扰素基因的刺激物（STING）结合以激活IFN-I。在这里，我们显示cGAMP在人类和小鼠细胞的炎症小体激活中具有非典型功能。炎性体激活需要两个信号，这两个信号均被cGAMP激活。单独使用cGAMP可以通过IFN-1增强炎性体成分的表达，从而提供启动信号。另外，当与启动信号结合时，cGAMP通过AIM2，NLRP3，ASC和caspase-1依赖性过程激活炎症小体。这两个cGAMP介导的功能 启动和激活，对STING有不同的要求。暂时地，IFN-I的cGAMP诱导先于炎性体激活，然后在IFN-I减弱时发生。在小鼠中，cGAS / cGAMP可同时扩增炎性小体和IFN-1以控制鼠巨细胞病毒。因此，cGAMP除了激活了IFN-1外，还激活了炎性体，并且需要将两者激活才能控制DNA病毒的感染。