A noncanonical function of cGAMP in inflammasome priming and activation.
A noncanonical function of cGAMP in inflammasome priming and activation.
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DOI：
10.1084/jem.20171749
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发表时间：
2017-12-04
期刊：
影响因子：
--
通讯作者：
Ting JP
中科院分区：
文献类型：
--
作者：
Swanson KV;Junkins RD;Kurkjian CJ;Holley-Guthrie E;Pendse AA;El Morabiti R;Petrucelli A;Barber GN;Benedict CA;Ting JP
IFN-I信号传导和炎性体激活是对抗多种病原体的两个重要先天途径。Swanson等人的研究表明，cGAMP除了激活IFN-I外，还激活炎性小体，并且两者的激活是控制DNA病毒感染所必需的。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传感器环鸟苷单磷酸腺苷（cGAMP）合成酶（cGAS）结合DNA并产生cGAMP， cGAMP又结合干扰素基因刺激因子（STING）激活IFN-I。在这里，我们发现cGAMP在人类和小鼠细胞的炎性体激活中具有非规范功能。炎性小体的激活需要两个信号，这两个信号都是由cGAMP激活的。cGAMP单独通过IFN-I增强炎性小体成分的表达，提供启动信号。此外，当与启动信号结合时，cGAMP通过AIM2、NLRP3、ASC和caspase-1依赖过程激活炎性体。这两种cgamp介导的功能，启动和激活，对STING有不同的要求。在时间上，cGAMP诱导IFN-I先于炎性体激活，然后在IFN-I减弱时发生。在小鼠中，cGAS/cGAMP通过扩增炎性体和IFN-I来控制小鼠巨细胞病毒。因此，cGAMP除了激活IFN-I外，还激活炎性体，而这两者的激活是控制DNA病毒感染所必需的。
IFN-I signaling and inflammasome activation are two innate pathways important for combatting a variety of pathogens. Swanson et al. show that cGAMP activates the inflammasome in addition to IFN-I, and that the activation of both is needed to control infection by a DNA virus. 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.
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影响因子：
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