Cleavage of the catalytic intermediate fine-tunes cGAS signalling

Abstract

Excessive activation of cyclic GMP-AMP synthase (cGAS) drives inflammatory and autoimmune diseases, but complete inhibition of cGAS signaling can compromise host defence. Here we show that cGAS signaling can be tuned through a previously unrecognized regulatory checkpoint. Bacterial cGAS generates cGAMP through a two-step mechanism involving release and rebinding of a 2'-5'-linked linear dinucleotide intermediate. We identify a CBASS-associated exonuclease (Exo) that selectively degrades this catalytic intermediate, establishing a threshold for cGAS activation while preserving immune function. This thresholding mechanism is conserved across domains of life: Exo suppresses human cGAS activity in vitro and in mammalian cells and attenuates cGAS-driven pathology in vivo. Our findings identify the catalytic intermediate surveillance as a conserved strategy for safeguarding cGAS signaling.