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 weakly 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. Despite that direct targeting of GSDME by GZMB is not efficient, GSDME can be cleaved by CASP3. Activation of CASP3 by GZMB 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 via GZMB/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]