Cyclic GMP–AMP signalling protects bacteria against viral infection

The cGAS–STING pathway is a central component of the cell-autonomous innate immune system in animals1,2. The cGAS protein (cyclic GMP–AMP synthase) is a sensor of cytosolic viral DNA and, upon DNA sensing, produces a cyclic GMP–AMP (cGAMP) signalling molecule that binds the STING protein and activates the immune response3–5. cGAMP production has also been detected in bacteria6, and in Vibrio cholerae has been shown to activate a phospholipase that degrades the inner bacterial membrane7; however, its biological role remains unknown. Here we show that cGAMP signalling is part of an anti-phage defence system that is common in bacteria. This system is composed of a four-gene operon that codes for the bacterial cGAS, the associated phospholipase, and two enzymes with the eukaryotic-like domains E1/E2 and JAB. We show that this operon confers resistance against a wide array of phages. Phage infection triggers cGAMP production, which, in turn, activates the phospholipase leading to loss of membrane integrity and cell death before completion of phage reproduction. Diverged versions of this system appear in more than 10% of prokaryotic genomes, and we show that variants with effectors other than phospholipase also protect against phage infection. Our results suggest that the eukaryotic cGAS–STING antiviral pathway has ancient evolutionary roots in microbial defence against phages.