GSDME (1-270) binds cardiolipin

Gasdermin E (GSDME) is cleaved by caspase 3 (CASP3) at D270 in response to apoptotic stimuli (Rogers C et al. 2017; Wang Y et al. 2017). The released N‑terminal fragment of GSDME (1‑270) targets the plasma membrane to drive pyroptosis in GSDME‑expressing cells (Wang Y et al. 2017). In addition, the N‑terminal fragment of mouse GSDME binds to cardiolipin liposomes causing severe leakage (Wang Y et al. 2017). Although cardiolipin is primarily located in the inner mitochondrial membrane, the outer mitochondrial membrane also contains around 10‑20% cardiolipin and cardiolipin translocates in a regulatable manner between the compartments (Liu J et al. 2003; reviewed in Dudek J 2017). Confocal microscopy and biochemical analysis revealed that tagged‑GSDME (1‑270) localized to mitochondria and triggered release of proapoptotic proteins such as cytochrome c (CYCS) upon ectopic expression in human HeLa cells or human embryonic kidney 293T (HEK293T) cells (Rogers C et al. 2019). Endogenous GSDME (1‑270) also localized to the mitochondrial fraction during apoptosis in TNFα plus actinomycin D (TNFα/actD)‑treated human lymphoid CEM‑C7 cells. Apoptotic stimuli‑triggered cleavage of GSDME (1‑270) induced CYCS release and ROS production in CEM‑C7 cells (Rogers C et al. 2019). These data suggest that the N‑terminal fragment of GSDME (1‑270) can permeabilize the mitochondria in response to apoptotic stimuli (Rogers C et al. 2019), however, the physiological relevance of this event remains to be determined.<p>This Reactome event describes the GSDME (1‑275) binding to mitochondrial cardiolipin leading to CYCS release from the mitochondria.

Gasdermin E (GSDME) 在细胞凋亡刺激（Rogers C 等人，2017；Wang Y 等人，2017）作用下，被caspase 3 (CASP3) 在D270位点切割。GSDME释放的N端片段（1-270）靶向质膜，从而驱动表达GSDME的细胞发生焦亡（Wang Y 等人，2017）。此外，小鼠GSDME的N端片段与心磷脂脂质体制结合，导致严重泄漏（Wang Y 等人，2017）。尽管心磷脂主要位于线粒体内膜，但线粒体外膜也含有约10-20%的心磷脂，且心磷脂在细胞器之间以可调节的方式发生转运（Liu J 等人，2003；Dudek J 综述，2017）。共聚焦显微镜和生化分析揭示了标记的GSDME（1-270）定位于线粒体，并在人类HeLa细胞或人类胚胎肾293T（HEK293T）细胞中异位表达时触发促凋亡蛋白如细胞色素c（CYCS）的释放（Rogers C 等人，2019）。内源性GSDME（1-270）在TNFα加放线菌素D（TNFα/actD）处理的人类淋巴细胞CEM-C7细胞凋亡过程中也定位于线粒体组分。细胞凋亡刺激触发的GSDME（1-270）切割导致CYCS释放和ROS产生于CEM-C7细胞（Rogers C 等人，2019）。这些数据表明，GSDME（1-270）的N端片段可以响应细胞凋亡刺激而使线粒体通透化（Rogers C 等人，2019），然而，此事件的生理相关性尚待确定。《Reactome》事件描述了GSDME（1-275）与线粒体心磷脂结合，导致线粒体中CYCS的释放。