Gasdermin D mediates a fast transient release of ATP after NLRP3 inflammasome activation before ninjurin 1-induced lytic cell death

Abstract

Pyroptosis is a lytic cell death triggered by the cleavage of gasdermin (GSDM) proteins and subsequent poreformation by the N-terminal domain oligomerization in the plasma membrane. GSDMD is cleaved by caspase-1/-4/-5/-11 upon inflammasome activation and mediates interleukin (IL)-1b and IL-18 release.GSDMD pores favor ninjurin 1 (NINJ1)-induced plasma membrane rupture and cell death. Here, we demonstratethat GSDMD mediates early ATP release upon NLRP3 inflammasome activation independently ofNINJ1, occurring before IL-1b release and cell death and constituting an early danger signal. The releaseof ATP is a transient signal terminated before the cells continue to permeabilize and die. The differentN termini of GSDMA to -E are also able to release ATP and induce monocyte migration toward pyroptoticcells. This study reveals ATP release as an early and transient danger signal depending on GSDMD plasmamembrane permeabilization, independently of the late stages of lytic cell death.