FAD is an immune checkpoint metabolite for cGAS and RIG-I

“Our laboratory has long been interested in how endogenous metabolites finetune innate immunity. We hypothesized that abundant, evolutionarily conserved metabolites might serve as endogenous ‘brakes’ on the sensors cGAS and RIG-I to restrain their activation under physiological conditions, while enabling rapid activation upon infection,” explains Weina Zhang, a co-corresponding author of the study, and lead contact.

The authors first screened a library of endogenous metabolites in vitro for their capacity to block interferon expression upon cytosolic nucleic acid exposure. FAD emerged as a hit that elicited a dose-dependent inhibition on stimulation of cGAS or RIG-I signaling specifically. Subsequent mechanistic studies confirmed that FAD acts at the sensor level, rather than downstream. Using binding, mutation, colocalization microscopy and structure prediction assays, the authors revealed FAD as a specific inhibitor of both cGAS and RIG-I that is able to bind in their sufficiently spacious catalytic pockets to block cGAMP production and ATPase activity, respectively.

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