Figure 2.

Molecular mechanisms of pyroptotic cell death (16). (A) The sensing of cytosolic disturbances by NLRP3 (NLR family pyrin domain-containing 3) receptor recruits the adaptor protein apoptosis-associated speck-like protein containing (ASC) to a large aggregate platform (called the inflammasome) that serves as a site of caspase-1 activation. Active caspase-1 cleaves the 53-kDa GSDMD and generates a 31-kDa N-terminal pore-forming fragment that controls pyroptosis(Canonical model). GSDMD can also be processed via inflammasome-independent activation of caspase-11(Non-canonical model). In this pathway, caspase-11 in mice and caspase-4 and 5 in humans bind to and are activated by LPS released into the cytoplasm after gram-negative bacterial infection. Unlike cleaved caspase-1, cleaved caspase-11 does not convert pro-IL-1β and pro-IL-18 to their mature forms. Instead, the process of pyroptosis promotes K+ efflux to activate caspase-1-dependent maturation of the pro-inflammatory cytokines IL-1β and IL-18 after NLRP3 inflammasome activation, leading to cellular pyroptosis. (B) Besides GSDMD, there is also a gasdermin E (GSDME)-dependent pyroptosis. GSDME is cleaved by caspase-3 upon mitochondrial dysfunction or death receptor activation. The GSDME N-fragments promote cell swelling and lysis by forming pores in the plasma membrane. ASC, apoptosis-associated speck-like protein containing; LPS: lipopolysaccharide. Reproduced with permission from [Ketelut-Carneiro N, Fitzgerald KA. Apoptosis], [Pyroptosis, and Necroptosis-Oh My! The Many Ways a Cell Can Die.]; published by [J Mol Biol], [2022].