TY - JOUR
T1 - A noncanonical function of cGAMP in inflammasome priming and activation
AU - Swanson, Karen V.
AU - Junkins, Robert D.
AU - Kurkjian, Cathryn J.
AU - Holley-Guthrie, Elizabeth
AU - Pendse, Avani A.
AU - Morabiti, Rachid El
AU - Petrucelli, Alex
AU - Barber, Glen N.
AU - Benedict, Chris A.
AU - Ting, Jenny P.Y.
N1 - Funding Information:
We acknowledge the Microscopy Services Laboratory within the UNC Core Services, where all confocal microscopy experiments were performed. This work is supported by the U.S. National Institutes of Health (NIH) U19 AI109965, AI067798, and R37 AI029564 to J.P.-Y. Ting; NIH RO1 AI101423 to C.A. Benedict; NIH T32 AI007151 to R.D. Junkins; NIH T32 AI07273 to C.J. Kurkjian; and NIH T32 CA009156 and American Cancer Society PF-15-047-01-MPC to A.A. Pendse. The authors declare no competing financial interests.
Funding Information:
This work is supported by the U.S. National Institutes of Health (NIH) U19 AI109965, AI067798, and R37 AI029564 to J.P.-Y. Ting; NIH RO1 AI101423 to C.A. Benedict; NIH T32 AI007151 to R.D. Junkins; NIH T32 AI07273 to C.J. Kurkjian; and NIH T32 CA009156 and American Cancer Society PF-15-047-01-MPC to A.A. Pendse. The authors declare no competing financial interests.
Publisher Copyright:
© 2017 Swanson et al.
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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 (STI N G) 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 STI N G. 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.
AB - 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 (STI N G) 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 STI N G. 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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U2 - 10.1084/jem.20171749
DO - 10.1084/jem.20171749
M3 - Article
C2 - 29030458
AN - SCOPUS:85036585683
VL - 214
SP - 3611
EP - 3262
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 12
ER -