Fig. 2

Molecular mechanism of pyroptosis. Caspase-1-dependent pyroptosis requires activation of the canonical inflammasomes. In this pathway, pathogen-associated molecular patterns activate their respective inflammasome sensors, including NLRP3, NLRP1, NLRC4, AIM2, and Pyrin. These inflammasomes recruit ASC adaptors, and the NLR or AIM2 signaling domains are connected to the ASC through homotypic interactions which generates the formation of ASC focus. The ASC focus recruits procaspase-1, leading to the activation of caspase-1. Noncanonical inflammasome direct recognition of the cytosolic lipopolysaccharide (LPS), which is derived from gram negative bacteria and can directly bind to and active caspase-4/5/11. GSDMD is the direct substrate of caspase-1/4/5/11, which can be specifically cleaved by inflammatory caspase and plays an important role in the downstream of inflammatory caspase. GSDMD exists in an autoinhibitory conformation at homeostasis, in which the inhibitory C terminal domain (C-GSDMD) retains the pore-forming N terminal domain (N-GSDMD) in an inactive state. Upon processing by the activated caspases, the GSDMD N terminal is released and translocated to the inner plasma membrane. Activated caspase-1 also cleave and activate the proinflammatory cytokines interleukin (IL)-1β and IL-18, which are released through GSDMD pores