AA467197 controls the hyperactivation of the NLRP3 inflammasome during infection

The hyperactivation of NLRP3 plays an essential role during infections, in which case a small portion of GSDMD is processed to become active and IL-1β is secreted for a long duration. However, the mechanism underlying NLRP3 hyperactivation remains unclear. Here we took use of the CRISPR/Cas9 technology to screen for genes involved in NLRP3 hyperactivation. We discovered that AA467197 suppresses the NLRP3 inflammasome to a hyperactivation state, and without affecting the canonical NLRP3 inflammasome activation. During infections caused by low doses of pathogens, AA467197 deficient cells have elevated rates of cell death compared with wild-type controls. Mechanistically, AA467197 binds to GSDMD and hinders its processing by the oligomerized caspase-1. Cells deficient for AA467197 undergo canonical NLRP3 inflammasome activation when encountering low-dose infections, leading to severe GSDMD cleavage and cell pyroptosis. Our results uncover a molecular mechanism for the exquisite regulation of the NLRP3 inflammasome in a hyperactivated state, which might be useful for further clinical treatment of infections.