Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway

TLDR

DNA in the cytoplasm is a danger signal that triggers type I interferon production through the cGAMP–STING pathway. Biochemical fractionation and quantitative mass spectrometry identified a nucleotidyltransferase family enzyme, cGAS, that synthesizes cGAMP. cGAS functions as a cytosolic DNA sensor that binds DNA, produces cGAMP, and activates IRF3/IFN‑β signaling in a STING‑dependent manner.

Abstract

The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers host immune responses such as the production of type I interferons. Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-β in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-β induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.