Fig. 8.

Lethal toxin and Salmonella use distinct mechanisms to elicit the common pathway of caspase-1-dependent pyroptosis. (Upper) The LT complex consisting of PA and LF is taken up by macrophages in a Ca²⁺-dependent manner. Endosome acidification, which is blocked by NH₄Cl, triggers a conformational change in PA, allowing translocation of LF into the cytosol. The Ca²⁺ channel blocker verapamil also inhibits LF translocation. In the cytosol, LF proteolytically cleaves MEK and other substrates, after which caspase-1 activation requires proteasome activity, potassium efflux, and the inflammasome protein Nalp1. Salmonella infection stimulates caspase-1 by an independent pathway requiring ligand(s) delivered by the bacterial type III secretion system (T3SS) and the inflammasome protein Ipaf. (Lower) Caspase-1 activated by both stimuli mediates a common pathway of pyroptosis: cell death featuring DNA fragmentation, secretion of activated inflammatory cytokines, and lytic release of inflammatory intracellular contents mediated by the formation of membrane pores between 1.1 and 2.4 nm in diameter. Osmotic lysis during pyroptosis is blocked by osmoprotectants and the cytoprotective agent glycine.