Apoptotic caspase-7 activation inhibits non-canonical pyroptosis by GSDMB cleavage

Abstract

GSDMB is associated with several inflammatory diseases, such as asthma, sepsis and colitis. GZMA is released by cytotoxic lymphocytes and cleaves GSDMB at the K244 site and to induce GSDMB N-terminus dependent pyroptosis. This cleavage of GSDMB is noncell autonomous. In this study, we demonstrated that the GSDMB-N domain (1-91 aa) was important for a novel cell-autonomous function and that GSDMB could bind caspase-4 and promote noncanonical pyroptosis. Furthermore, activated caspase-7 cleaved GSDMB at the D91 site to block GSDMB-mediated promotion of noncanonical pyroptosis during apoptosis. Mechanistically, the cleaved GSDMB-C-terminus (92-417 aa) binds to the GSDMB-N-terminus (1-91 aa) to block the function of GSDMB. During E. coli and S. Typhimurium infection, inhibition of the caspase-7/GSDMB axis resulted in more pyroptotic cells. Furthermore, in a septic mouse model, caspase-7 inhibition or deficiency in GSDMB-transgenic mice led to more severe disease phenotypes. Overall, we demonstrate that apoptotic caspase-7 activation inhibits non-canonical pyroptosis by cleaving GSDMB and provide new targets for sepsis therapy.