Beyond sensing DNA: a role for cGAS in the detection of extracellular cyclic di-nucleotides

Cyclic GMP‐AMP synthase (cGAS) is best known as an innate immune receptor that detects pathogen DNA in the cytosol. In this issue of EMBO Reports, Kaufmann and colleagues 1 report that cGAS has an additional role in innate immunity: it can also bind cyclic di‐nucleotides (CDNs), signalling molecules produced by bacteria. The authors show that when extracellular CDNs are taken up by endocytosis, they bind to cGAS, causing it to form a complex with the CDN receptor STING (STimulator of INterferon Genes), thereby enhancing its activation. As cGAS is dispensable for the detection of intracellular CDNs, this work exemplifies how the localisation of pathogen‐associated molecular patterns (PAMPs) influences innate immune signalling.