The stress granule protein G3BP1 promotes pre-condensation of cGAS to allow rapid responses to DNA

Cyclic GMP-AMP synthase (cGAS) functions as a key sensor for microbial invasionding and cellular damage by detecting the emergingence of cytosolic DNA. Here, we report that GTPase-activating protein-(SH3 domain)-binding protein 1 (G3BP1) primes cGAS for its prompt activation by engaging cGAS in a primary liquid-phase condensation state. With Using high-resolution microscopy, we show that in resting cells, cGAS exhibits a particle-like morphological characteristicss, which areis markedly weakened when G3BP1 is deleted. Upon DNA challenge, the pre-condensed cGAS undergoes liquid-liquid phase separation (LLPS) much more efficiently. Importantly, G3BP1 deficiency or its inhibition dramatically diminisheses the DNA-induced LLPS and the subsequent activation of cGAS. Interestingly, RNA, is previously reported to form LLPS condensates with cGAS, but does not activate cGAS. Accordingly, wWe find that DNA-, but not RNA-, treatment leads to the dissociation of G3BP1 from cGAS. Taken together, our study reveals shows that a the primary G3BP1-indcued condensation state of cGAS is critical for its expeditious rapid response to DNA.