DNA-induced liquid phase condensation of cGAS activates innate immune signaling

The binding of DNA to cyclic GMP-AMP synthase (cGAS) leads to the production of the secondary messenger cyclic GMP-AMP (cGAMP), which activates innate immune responses. Here, we show that DNA binding to cGAS robustly induced the formation of liquid-like droplets in which cGAS was activated. The disordered and positively charged cGAS N-terminus enhanced cGAS–DNA phase separation by increasing the valencies of DNA binding. Long DNA was more efficient in promoting cGAS liquid phase separation and cGAS enzyme activity than short DNA. Moreover, free zinc ion enhanced cGAS enzyme activity both in vitro and in cells by promoting cGAS–DNA phase separation. These results demonstrated that the DNA-induced phase transition of cGAS promotes cGAMP production and innate immune signaling.