cGAMP-activated cGAS–STING signaling: its bacterial origins and evolutionary adaptation by metazoans

The metazoan cGAMP-activated cGAS–STING innate immunity pathway is triggered in response to genomic instability and DNA damage, thereby providing host defense against microbial pathogens. This pathway also impacts on autophagy, cellular senescence and antitumor immunity, while its overactivation triggers autoimmune and inflammatory diseases. Metazoan cGAS generates cGAMP containing distinct combinations of 3′-5′ and 2′-5′ linkages, which target the adaptor protein STING and activate the innate immune response through a signaling cascade leading to upregulation of cytokine and interferon production. This Review highlights a structure-based mechanistic perspective of recent advances in cGAMP-activated cGAS–STING innate immune signaling by focusing on the cGAS sensor, cGAMP second messenger and STING adaptor components, thereby elucidating the specificity, activation, regulation and signal transduction features of the pathway. In addition, the Review addresses progress towards identification of inhibitors and activators targeting cGAS and STING, as well as strategies developed by pathogens to evade cGAS–STING immunity. Most importantly, it highlights cyclic nucleotide second messengers as ancient signaling molecules that elicit a potent innate immune response that originated in bacteria and evolved through evolutionary adaptation to metazoans. In this Review, the authors provide a comprehensive overview of recent structural studies of the cGAS–STING complex, discussing pertinent functional and mechanistic implications.