Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin
Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin
复制标题
DOI：
10.1038/nature22393
复制
发表时间：
2017-07-06
期刊：
影响因子：
64.8
通讯作者：
Shao, Feng
中科院分区：
文献类型：
--
作者：
Wang, Yupeng;Gao, Wenqing;Shao, Feng
上睑下垂是细胞死亡的一种形式，对免疫至关重要。它可由典型的caspase-1炎性小体或由胞内脂多糖(1-3)激活caspase-4、-5和-11而诱导。Caspase将Gasdermin D(GSDMD)切割在其中间连接子上，在其Gasdermin-N结构域上释放自抑制作用，该结构域通过其成孔活性(4-9)执行下垂。GSDMD属于Gasdermin家族，具有相同的成孔结构域(4，6，10)。其他气体蛋白的功能和激活机制尚不清楚。在这里，我们发现GSDME，最初被鉴定为DFNA5(耳聋，常染色体显性遗传5)(11)，可以将caspase-3介导的由肿瘤坏死因子或化疗药物诱导的细胞凋亡转换为下垂。GSDME被其连接子中的caspase-3特异性切割，产生穿透膜的GSDME-N片段，从而诱导下睑下垂。化疗后，caspase-3对GSDME的切割导致某些表达GSDME的癌细胞发生下垂。GSDME在大多数癌细胞中沉默，但在许多正常组织中表达。人原代细胞在化疗药物激活caspase-3后表现出依赖GSDME的上睑下垂。Gsdme(-/-)(也称为Dfna5(-/-))小鼠受到保护，免受化疗引起的组织损伤和体重减轻。这些发现表明，caspase-3的激活可以通过裂解GSDME来触发坏死，并为癌症化疗提供了新的见解。
Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide(1-3). The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity(4-9). GSDMD belongs to a gasdermin family that shares the pore-forming domain(4,6,10). The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5)(11), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced 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 activation of caspase-3 by chemotherapy drugs. Gsdme(-/-) (also known as Dfna5(-/-)) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.