Chemotherapy-Activated Caspase 3 Cleaves GSDME to Drive Pyroptosis

In response to pathogen infiltration, the inflammatory caspases 1, 4, 5, and 11 are activated and cleave gasdermin D (GSDMD) to generate the GSDMD–N terminal domain, which induces pyroptosis, the inflammatory form of programmed cell death of immune cells, and the subsequent release of inflammatory cytokines. Recent evidence suggests that the loss of GSDME, a deafness gene which is also a potential candidate tumor suppressor that is silenced in many cancer types by promoter methylation, may mediate resistance to etoposide in melanoma. To further elucidate the function of GSDME and the mechanism underlying GSDME activation, Wang, Gao, and colleagues evaluated the role of GSDME in chemotherapy-mediated cell death. Expression of GSDME or GSDMD expressing a caspase 3 (CASP3)–cleavage site (GSDMD^DEVD) resulted in the switch from apoptosis to pyroptosis in response to chemotherapy. Further, both GSDME and GSDMD^DEVD were cleaved by activated CASP3 to produce the pyroptotic GSDM N-terminal domain and induce pyroptosis, and the asparagine 270 residue was identified as the CASP3 cleavage site in GSDME. Similarly, overexpression of GSDME harboring a mutation in the CASP3 cleavage site resulted in CASP3-dependent apoptosis and not pyroptosis after treatment with chemotherapy drugs, whereas normal cells with endogenous GDSME underwent CASP3-dependent pyroptosis in response to chemotherapy. Unlike wild-type Gsdme mice, Gsdme knockout mice did not exhibit chemotherapy-induced toxicity after treatment with cisplatin or bleomycin. Taken together, these results further describe the biology of another gasdermin, show that CASP3 can mediate pyroptosis, and suggest that modulation of GSDME expression may improve the antitumor efficacy and decrease the toxicity of chemotherapeutic drugs.

Wang Y, Gao W, Shi X, Ding J, Liu W, He H, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavag of a Gasdermin. Nature 2017 May 1 [Epub ahead of print].