燃料蛋白E（也称为DFNA5）被鉴定为活化的Caspase-3（Casp3）的基材，凋亡细胞死亡的刽子手胱天级（Wang Y等人。2017; Rogers C等人2017）。GSDME可以将TNF或化疗药物诱导的CASP3介导的凋亡与二次坏死/糊化酶（Wang Y等。2017; rogers c等人2017;张Cc等，2019;张J等人。2020;张Z等人。2020;在江米等人审查2020）。GSDME的表达水平决定了细胞死亡的类型（王Y等，2017）。Casp3介导的GSDME的切割驱动GSDME表达细胞中的糊瘤，包括正常和某些类型的癌细胞，而缺乏足够的GSDME水平的细胞经历凋亡而不会进入糊酶或次要坏死（Wang Y等人2017;江泽民审查M等人。2020）。Casp3在ASP270后切割链接器中的GSDME，产生破坏细胞膜的GSDME N-末端片段GSDME（1-270），并诱导次要坏死/糊色细胞死亡（Wang Y等，2017; Rogers C等人2017）。GSDME D267A和GSDME D270A突变在TNF刺激的HELA细胞中抵抗裂解，并没有显示死亡切换活动（Wang Y等。2017）。GSDME抑制剂（Zdevd）在GSDME的人神经母细胞瘤SH-SY5Y（Zhang J等人，2020）和结肠癌HT-29和HCT116细胞（Yu J等，2019）治疗时，对GSDME的处理抑制用化学治疗药物。 Similarly, a specific CASP3 inhibitor and a pan‑caspase inhibitor (zVAD) suppressed drug‑induced GSDME(1-270) generation and reduced pyroptosis in human lung cancer A549 cells (Zhang CC et al. 2019; Zhang J et al. 2020). In addition, GSDME(1-270) was shown to permeabilize the mitochondrial membrane, releasing cytochrome c and activating the apoptosome in GSDME‑expressing human embryonic kidney (HEK293) cells (Rogers C et al. 2019). The release of cytochrome c and CASP3 activation in response to apoptotic stimuli were significantly reduced in GSDME‑deficient human T‑lymphoblastic (CEM‑C7) cells (Rogers C et al. 2019). Moreover, GSDME deficiency accelerated cell growth in human melanoma cell line (MeWo) and in mouse models of melanoma, colon (CT26) and breast (EMT6) tumors (Lage H et al. 2001; Zhang Z et al. 2020). Gsdme‑/‑ mice were protected from chemotherapy‑induced tissue damage (Wang Y et al. 2017). These data suggest that GSDME may have cytotoxic effects in tumor cells by triggering pyroptotic cell death. GSDME‑induced pyroptosis was shown to suppress tumor growth by increasing anti‑tumor functions of tumor‑infiltrating NK and CD8+ T killer lymphocytes (Zhang Z et al. 2020). Cancer‑related GSDME mutations significantly reduced lactate dehydrogenase (LDH) release, a hallmark of lytic cell death (Zhang Z et al. 2020). The tumor suppressor role of GSDME is further supported by studies showing reduced expression of GSDME due to increased methylation of the GSDME gene promoter in primary gastric tumors, colorectal adenocarcinomas and breast tumors (Akino K et al. 2006; Kim MS et al. 2008; Yokomizo K et al. 2012; Croes L et al. 2017; Ibrahim J et al. 2019). GSDME‑deficient tumors are associated with reduced survival in patients (reviewed in Xia X et al. 2019). Thus, CASP3 can induce pyroptosis and apoptosis in a manner that is dependent on the expression level of GSDME. GSDME was dispensable for the regulation of pyroptosis in human Jurkat T cells and THP‑1 monocytes (Tixeira R et al. 2018). In line with this study, GSDME was not required for pyroptosis in mouse Casp1‑and Casp11‑deficient bone marrow‑derived macrophages (BMDMs) treated with flagellin, cytochrome c or Fas ligand (Lee BL et al. 2018). Together, these findings suggest that factors in addition to the ones annotated here play a role in connecting apoptosis and pyroptosis, which has been shown in the context of PANoptosis (Karki R et al. 2021).

该反应的事件显示了D270的Casp3介导的GSDME的切割。