A noncanonical function of cGAMP in inflammasome priming and activation

J Exp Med. 2017 Dec 4;214(12):3611-3626. doi: 10.1084/jem.20171749. Epub 2017 Oct 13.


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.

MeSH terms

  • Animals
  • Cell Death / drug effects
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism
  • Inflammasomes / metabolism*
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / pharmacology
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Muromegalovirus / physiology
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Nucleotides, Cyclic / metabolism*
  • Nucleotidyltransferases / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • Aim2 protein, mouse
  • DNA-Binding Proteins
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Lipopolysaccharides
  • Membrane Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nucleotides, Cyclic
  • RNA, Messenger
  • Sting1 protein, mouse
  • cyclic guanosine monophosphate-adenosine monophosphate
  • DNA
  • Nucleotidyltransferases