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bioRxiv · 10.1101/2025.03.04.641389

An exonuclease safeguards cGAS immune signaling by degrading its 2'-5' phosphodiester intermediate

Zhu, B.·Yan, Y.·Yu, B.·Wang, H.·Zhao, X.·Wang, L.
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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.

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Zhu, B., Yan, Y., Yu, B., Wang, H., Zhao, X., Wang, L.. 2025-03-06. An exonuclease safeguards cGAS immune signaling by degrading its 2'-5' phosphodiester intermediate. https://doi.org/10.1101/2025.03.04.641389

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