Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA

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.