期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 12, 页码 3611-3626出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20171749
关键词
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资金
- U.S. National Institutes of Health (NIH) [U19 AI109965, AI067798, R37 AI029564]
- NIH [R01 AI101423, T32 AI007151, T32 AI07273, T32 CA009156]
- American Cancer Society [PF-15-047-01-MPC]
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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