Granzyme B (GZMB) belongs to a family of serine proteases stored in the cytotoxic granules of natural killer (NK) cells and cytotoxic T lymphocytes. GZMB cleaves recombinant gasdermin E (GSDME) in vitro and in lysates from GSDME‑overexpressing human embryonic kidney 293T (HEK293T) cells (Zhang Z et al. 2020). Mutational analysis suggests that GZMB activates GSDME at the same site (D270) as caspase‑3 (CASP3). In the presence of perforin (PFN), GZMB cleaved GSDME in human neuroblastoma SH‑SY5Y cells inducing pyroptotic cell death. Activation of CASP3 was also detected in GZMB +PFN ‑treated SH‑Y5Y cells (Zhang Z et al. 2020). In addition, human NK line YT or NK‑92 triggered pyroptosis in GSDME‑overexpressing HeLa cells in both CASP3‑dependent and ‑independent manners. The data suggest that GZMB released from killer cytotoxic lymphocytes may induce GSDME‑dependent lytic cell death in tumor targets by directly cleaving GSDME or via the CASP3‑mediated cleavage of GSDME (Zhang Z et al. 2020). Similar findings were reported for chimeric antigen receptor (CAR) T cells that release a large amount of PFN and GZMB and result in the activation of GSDME in B leukemic cells leading to cell pyroptosis (Liu Y et al. 2020).
serine-type endopeptidase activity of GZMB [cytosol]