Inflammasomes are multiprotein platforms which initiate innate immunity by activation and recruitment of caspase-1. The NLRP1B inflammasome is triggered upon cleavage by the anthrax toxin protease. The mechanism by which cleavage leads to NLRP1B activation is unknown. In this study, we find that a fragment that is a potent activator that is caspase-1 being, liberated by results in proteasome-mediated degradation of those amino-terminal domain names of NLRP1B. Proteasome-mediated degradation of NLRP1B is necessary and sufficient for activation. Consistent with our practical degradation model, we identify IpaH7.8, a Shigella flexneri ubiquitin ligase secreted effector, as an enzyme that induces NLRP1B degradation and activation. Our results provide a unified mechanism for activation by diverse activities.