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Received: 25 June 2019
Accepted: 11 September 2019
Published online: 18 September 2019
The cyclic GMP-AMP synthase (cGAS)-STlNG pathway is a central component of the cell-autonomous innate immune system in animals1,2. The cGAS protein is a sensor of cytosolic viral DNA and, upon sensing DNA, it produces a cyclic GMP-AMP (cGAMP) signalling molecule that binds to the STING protein and activates the immune response3-5. The production of cGAMP has also been detected in bacteria6, and has been shown, in Vibrio cholerae, to activate a phospholipase that degrades the inner bacterial membrane7. However, the biological role of cGAMP signalling in bacteria remains unknown. Here we show that cGAMP signalling is part of an antiphage defence system that is common in bacteria. This system is composed of a four-gene operon that encodes the bacterial cGAS and the associated phospholipase, as well as two enzymes with the eukaryotic-like domains E1, E2 and JAB. We show that this operon confers resistance against a wide variety of phages. Phage infection triggers the production of cGAMP, which-in turn-activates the phospholipase, leading to a loss of membrane integrity and to 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 that stem from microbial defences against phages.
Bacterial antiphage immune systems, such as CRISPR-Cas and restriction modification systems, tend to concentrate in 'defence islands' in bacterial genomes8; this property has facilitated the discovery of defence systems on the basis of their colocalization with known ones9-11. We noticed that homologues of the gene that encodes cGAS in V. cholerae (dncV; 'dinucleotide cyclase in Vibrio') frequently tend to appear near defence genes. Out of 637 homologues of this protein that we identified through a homology search in 38,167 microbial genomes, we found that 417 (65.5%) are located in the vicinity of known defence systems (Fig. 1a). It has previously been shown that such a high propensity of colocalization with defence genes is a strong predictor that the gene under inspection has a role in phage resistance11. These results therefore suggest that the gene that encodes...