Fig. 4.

Molecular mechanisms of gasdermins activation. In response to microbial invasion, canonical inflammasomes and in response to LPS, non-canonical inflammasomes, respectively, trigger the activation of inflammatory caspases—caspase-1, -4, -5, and -11, resulting in GSDMD cleavage and generation of GSDMD-NT, followed by the formation of GSDMD pores. GSDMD is also processed by NE and cathepsin G released from neutrophil granules. Yersinia infection initiates caspase-8 to cleave GSDMD. Additionally, the degradation of GSDMC and GSDME is achieved through the action of caspase-8 and caspase-3, respectively, contributing to the transition from apoptotic to pyroptotic cell death. Caspase-8 and cytochrome c are involved in caspase-3 activation. Killer cells secret GzmA and GzmB, which directly cleave GSDMB and GSDME, respectively, to provoke pyroptosis. Secreted by group A Streptococcus, SpeB functions as a cysteine protease that specifically targets GSDMA, thereby initiating the pathological cascade leading to pyroptosis. Caspase-1 can also cleave GSDMB, GSDMA, and GSDME