Pyroptosis, activated by the canonical caspase-1 inflammasomes or caspase-4/5/11 by cytosolic LPS, is critical for immunity(1,2,3). The caspases cleave Gasdermin D (GSDMD) in the middle linker to release autoinhibition on its Gasdermin-N domain that executes pyroptosis via the pore-forming activity(4,5,6,7,8,9). GSDMD belongs to a Gasdermin family sharing the pore-forming domain(4,6,10). The function and mechanism of activation for other Gasdermins are unknown. Here we show that GSDME, originally identified as DFNA5 (Deafness, Autosomal Dominant 5)(11), could switch TNFα or chemotherapy drugs-induced and caspase-3-mediated apoptosis to pyroptosis. GSDME was specifically cleaved by caspase-3 in the linker, generating a GSDME-N fragment that perforated membranes for pyroptosis induction. Following chemotherapy drugs treatment, caspase-3 cleavage of GSDME determined pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon caspase-3 activation by chemotherapy drugs. Gsdme(-/-) mice were protected from chemotherapy drugs-induced various tissue damages and weight loss. These findings bring an unexpected concept that caspase-3 activation can trigger necrosis through cleaving GSDME and offer new insights into cancer chemotherapy.
