cGAS facilitates sensing of extracellular cyclic dinucleotides to activate innate immunity

Cyclic dinucleotides (CDNs) are important second messenger molecules in prokaryotes and eukaryotes. Within host cells, cytosolic CDNs are detected by STING and alert the host by activating innate immunity characterized by type I interferon (IFN) responses. Extracellular bacteria and dying cells can release CDNs, but sensing of extracellular CDNs (eCDNs) by mammalian cells remains elusive. Here, we report that endocytosis facilitates internalization of eCDNs. The DNA sensor cGAS facilitates sensing of endocytosed CDNs, their perinuclear accumulation, and subsequent STING‐dependent release of type I IFN. Internalized CDNs bind cGAS directly, leading to its dimerization, and the formation of a cGAS/STING complex, which may activate downstream signaling. Thus, eCDNs comprise microbe‐ and danger‐associated molecular patterns that contribute to host–microbe crosstalk during health and disease. Synopsis cGAS senses internalized extracellular cyclic dinucleotides, thereby promoting the formation of a cGAS/STING complex to activate innate immune responses. eCDNs thus are microbe‐ and danger‐associated molecular patterns that contribute to host‐microbe crosstalk. Clathrin‐dependent endocytosis facilitates internalization of extracellular cyclic dinucleotides. Internalized extracellular cyclic dinucleotides (eCDNs) bind cGAS directly, inducing its dimerization. eCDNs promote DNA sensing by cGAS, and the formation of the cGAS/STING complex. Graphical Abstract cGAS senses internalized extracellular cyclic dinucleotides, thereby promoting the formation of a cGAS/STING complex to activate innate immune responses. eCDNs thus are microbe‐ and danger‐associated molecular patterns that contribute to host‐microbe crosstalk.