Vps4B controls caspase-1 dynamics at the ASC speck to drive inflammasome activation.

The activation of caspase-1 requires assembly of the ASC speck to control inflammatory responses and pyroptosis. However, the recruitment of caspase-1 into the ASC speck for activation remains unclear. Here, we identified the ATPase Vps4B as a central component of the inflammasome that endogenously interacts with ASC and caspase-1, contributing to the activation of NLRP3 and AIM2 inflammasomes. Mechanistically, the polymerization of NLRP3 and ASC triggers intracellular Ca2+ signaling, which recruits Vps4B to the ASC speck. Vps4B forms a ring-like structure encircling the ASC filament and catalyzes the disassembly and liberation of the used caspase-1 CARD domain. This process enables replenishment and renewal of the newly unoccupied ASC speck, facilitating continuous caspase-1 recruitment and activation, thereby contributing to host defense against Listeria dissemination and the maintenance of blood-brain barrier integrity in vivo. Our study identifies a self-rejuvenating inflammasome process that opens up new avenues for therapeutic intervention in inflammatory diseases.