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

Cyclic G/AMP Synthase (cGAS) initiates inflammatory responses against pathogenic double-stranded (ds)DNA. Although it is well established that cGAS forms phase-separated condensates with dsDNA, their function remains poorly defined. We report here that the dimerization of cGAS on dsDNA creates a mesh-like network, leading to gel-like condensate formation. Although 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, which single-stranded RNA can dissolve and deactivate the enzyme. Moreover, gel-like, but not liquid-like, condensation not only protects bound dsDNA from exonucleases, but also limits the mobility of NTPs and the dinucleotide intermediate for efficient cGAMP synthesis. Together, our results show that enzymes can finetune surrounding microenvironments to regulate their signaling activities.