LAUSR

Significance The negative feedback system that tempers inflammasome activation and downstream inflammation remains unknown. To date, there has been intensive study of the role of Gasdermin D as a central player in executing pyroptosis, the cell death pathway downstream of inflammasome activation. We now unexpectedly found that the N-terminal fragment of Gasdermin D can also directly target and inhibit caspase-1/11, the effector caspases in inflammasome pathways, and so suppress downstream triggering of inflammation. We further identify the RFWK motif of the β1-β2 loop of the N-terminal fragment as a critical molecular feature for manifesting the inhibitory effects on caspase-1/11 activity. We also designed a molecule based on the RFWK motif that shows strong antiinflammatory efficacy.