Yupeng Wang, Wenqing Gao, et al.
Nature 2017
Pyroptosis is a form of cell death that is critical for immunity. The recent identification of GSDMD as the pyroptotic substrate of caspase-1, -4, -5 and -11 and of the conserved gasdermin family has redefined pyroptosis as gasdermin-mediated programmed necrosis. In this paper, the researchers found that GSDME, which was originally identified as DFNA5(deafness, autosomal dominant 5), could switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis.
First, They treated cell lines overexpressed with or knock out GSDME with TNFa plus cycloheximide(CHX), causing an apoptosis-to-pyroptosis switch, which resembled the function of GSDMD. Further experiments in vitro showed that GSDME was specifically cleaved by caspase-3 in its linker, generating aGSDME-N fragment that perforated membranes and thereby induced pyroptosis. And after chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis incertain GSDME-expressing cancer cells. To test whether GSDME contributes to the adverse effects of chemotherapy drugs in vivo, they generated Gsdme−/− mice. After peritoneal injection of cisplatin, Gsdme−/− mice were often more healthy and vigorous than wild-type mice. Cisplatin severely disrupted the crypts and villi and caused massive immune cell infiltration into the small intestine of wild-type mice, and these effects were attenuated in Gsdme−/−mice.These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.
DOI:10.1038/nm.3085