NLRP1 recognizes P. aeruginosa and C. diphtheriae through the RSR. DT and ExoA exotoxins ADP-ribosylate eukaryotic translation elongation factor 2 (EEF2) to inhibit protein synthesis and induce ribosome collisions that activate the MAP kinase kinase kinase ZAKα, initiating a signaling cascade culminating in p38α and p38β phosphorylation. Both ZAKα and p38α/β phosphorylate NLRP1’s N-terminal “tripwire,” leading to its functional degradation. The bioactive C terminus of NLRP1 complexes with ASC and CASP1 to form an active inflammasome and drive subsequent inflammation and pyroptotic cell death.