The cGAS-STING pathway for DNA sensing

Abstract

The nucleotidyl transferase cGAS, its second-messenger product cGAMP, and the cGAMP sensor STING form the basic mechanism of DNA sensing in the cytoplasm of mammalian cells. Several new reports now uncover key structural features associated with DNA recognition by cGAS and the catalytic mechanisms of cGAMP generation. Concurrent studies also reveal unique phosphodiester linkages in endogenous cGAMP that distinguish it from microbial cGAMP and other cyclic dinucleotides. Together, these studies provide a new perspective on DNA recognition in the innate immune system.

Fig. 1. The cGAS-STING pathway for DNA sensing

cGAS binds dsDNA using a “zinc thumb” structure and a positively charged surface. DNA-association induces a structural switch that repositions the catalytic residues to bind the GTP and ATP substrates mediated by magnesium ions. The catalysis proceeds from a 2′-5′ GpA linkage to a 3′-5 ApG linkage and forms a cyclic di-nucleotide 2′3′-cGAMP, which then binds and initiates large structural rearrangements in STING. The resulting STING-cGAMP complex may then promote TBK1 and IRF3 activation through its CTT. The zinc and magnesium ions that bind cGAS are colored cyan and green, respectively. The 2′3′-cGAMP is shown as spheres bound to STING.