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

DNA Sensing Is a (c)GAS DNA is normally localized to the nucleus, and so its cytoplasmic localization sends off alarm bells to the immune system because it indicates that a virus may have entered. But how does the immune system actually detect the DNA (see the Perspective by O'Neill)? Sun et al. (p. 786, published online 20 December) identify cyclic GMP-AMP (cGAMP) cyclase (cGAS), which can bind to cytoplasmic DNA directly and catalyze the production of cGAMP. cGAMP then acts as a second messenger to activate downstream signaling events that trigger antiviral immunity. Wu et al. (p. 826, published online 20 December) show that cGAMP, produced in response to cytoplasmic DNA, binds to and activates the signaling adaptor protein STING. Cyclic guanosine monophosphate–adenosine monophosphate synthase is identified and shown to be activated by DNA, but not RNA, in mammalian cells. [Also see Perspective by O'Neill] 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.

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