Dimerization-dependent gel-like condensation with dsDNA underpins the activation of human cGAS

Cyclic G/AMP (cGAMP) synthase (cGAS) initiates inflammatory responses against pathogenic double-stranded (ds)DNA. Although it is well established that cGAS forms phase-separated condensates with dsDNA, its function remains poorly defined. We report here that the dimerization of cGAS on dsDNA creates a mesh-like network, leading to hydrogel-like condensate formation. While cGAS binds to and forms condensates with various nucleic acids, only dsDNA permits the dimerization necessary for activation and gelation. cGAS co-condenses dsDNA and other nucleic acids but retains a distinct dsDNA-mediated gel-like substate that can be dissolved by single-stranded RNA or short dsDNA. Moreover, compared with liquid-like condensates, we find that gel-like condensates are more effective not only in protecting bound dsDNA from exonucleases but also in limiting the mobility of nucleoside triphosphates and the dinucleotide intermediate for cGAMP synthesis. Together, our results show that enzymes can fine-tune surrounding microenvironments to regulate their signaling activities.