Department of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.
Nat Commun. 2019 Apr 11;10(1):1689. doi: 10.1038/s41467-019-09397-2.
Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that GSDME-N also permeabilizes the mitochondrial membrane, releasing cytochrome c and activating the apoptosome. Cytochrome c release and caspase-3 activation in response to intrinsic and extrinsic apoptotic stimuli are significantly reduced in GSDME-deficient cells comparing with wild type cells. GSDME deficiency also accelerates cell growth in culture and in a mouse model of melanoma. Phosphomimetic mutation of the highly conserved phosphorylatable Thr6 residue of GSDME, inhibits its pore-forming activity, thus uncovering a potential mechanism by which GSDME might be regulated. Like GSDME-N, inflammasome-generated gasdermin D-N (GSDMD-N), can also permeabilize the mitochondria linking inflammasome activation to downstream activation of the apoptosome. Collectively, our results point to a role of gasdermin proteins in targeting the mitochondria to promote cytochrome c release to augment the mitochondrial apoptotic pathway.
Gasdermin E (GSDME/DFNA5) 被 caspase-3 切割后释放出 GSDME-N 结构域，该结构域通过在质膜上形成孔介导细胞焦亡。在这里，我们表明 GSDME-N 还会使线粒体膜通透，释放细胞色素 c 并激活凋亡体。与野生型细胞相比，GSDME 缺陷细胞对内在和外在凋亡刺激的细胞色素 c 释放和 caspase-3 激活反应明显降低。GSDME 缺陷还会加速培养中的细胞和黑色素瘤小鼠模型中的细胞生长。GSDME 的高度保守可磷酸化 Thr6 残基的磷酸模拟突变抑制其成孔活性，从而揭示了 GSDME 可能受到调控的潜在机制。与 GSDME-N 一样，炎性体生成的 gasdermin D-N (GSDMD-N) 也可以使线粒体通透，将炎性体激活与下游凋亡体激活联系起来。总之，我们的结果表明 gasdermin 蛋白在靶向线粒体以促进细胞色素 c 释放以增强线粒体凋亡途径方面发挥作用。
