Microbial pathogens can be detected by inflammasomes that induce inflammation and programmed cell death. Inflammasomes are sensors that survey cells for signs of compromise. One of these sensors, NLRP1, detects anthrax lethal toxin; however, the mechanism of NLRP1 activation has remained unknown. Here, Xu et al discover NLRP1 cleavage by lethal toxin induces the N-end rule, which targets NLRP1 for degradation. Surprisingly, the active inflammasome fragment escapes the proteasome and becomes an activate inflammasome itself.