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首页> 外文期刊>Apoptosis >Necrosis-like death can engage multiple pro-apoptotic Bcl-2 protein family members
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Necrosis-like death can engage multiple pro-apoptotic Bcl-2 protein family members

机译：坏死样死亡可参与多个促凋亡的Bcl-2蛋白家族成员

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摘要

Necroptosis is a physiologically relevant mode of cell death with some well-described initiating events, but largely unknown executioners. Here we investigated necrostatin-1 (Nec-1) sensitive death elicited by different necroptosis stimuli in L929 mouse fibrosarcoma cells, mouse embryonic fibroblasts (MEF) and bone marrow-derived macrophages. We found that TNFα- or zVAD-induced necroptosis occurs independently of the recently implicated executioners Bmf or PARP-2, but can involve the Bcl-2 family proteins Bid and Bak. Furthermore, this type of necroptosis is associated with mitochondrial cytochrome c release and partly sensitive to cyclosporine A inhibition, suggesting a cross talk with the mitochondrial permeability transition pore. Necroptosis triggered by cadmium (Cd) exposure caused fully Nec-1-sensitive and caspase-independent death in L929 cells that was associated with autocrine TNFα-mediated feed-forward signalling. In MEF Cd-exposure elicited a mixed mode of cell death that was to some extent Nec-1-sensitive but also displayed features of apoptosis. It was partly dependent on Bmf and Bax/Bak, proteins typically considered to act pro-apoptotic, but ultimately insensitive to caspase inhibition. Overall, our study indicates that inducers of “extrinsic” and “intrinsic” necroptosis can both trigger TNF-receptor signalling. Further, necroptosis may depend on mitochondrial changes engaging proteins considered critical for MOMP during apoptosis that ultimately contribute to caspase-independent necrotic cell death.
机译：坏死性坏死是一种与细胞死亡有关的生理学相关模式，具有一些已描述的启动事件，但执行者很大程度上未知。在这里，我们调查了由L929小鼠纤维肉瘤细胞，小鼠胚胎成纤维细胞（MEF）和骨髓源性巨噬细胞中不同的坏死病刺激引起的necrostatin-1（Nec-1）敏感死亡。我们发现，TNFα或zVAD诱导的坏死病独立于最近涉及的execution子手Bmf或PARP-2而发生，但可能涉及Bcl-2家族蛋白Bid和Bak。此外，这种坏死病与线粒体细胞色素C的释放有关，并且对环孢霉素A的抑制作用部分敏感，表明与线粒体通透性转换孔的相互作用。镉（Cd）暴露引发的坏死病导致L929细胞完全Nec-1敏感性和caspase非依赖性死亡，这与自分泌TNFα介导的前馈信号有关。在MEF中，镉暴露引起细胞死亡的混合模式，在某种程度上对Nec-1敏感，但也显示出细胞凋亡的特征。它部分地依赖于Bmf和Bax / Bak，这些蛋白质通常被认为具有促凋亡作用，但最终对caspase抑制不敏感。总体而言，我们的研究表明“外在”和“内在”坏死病的诱导剂均可触发TNF受体信号传导。此外，坏死性坏死可能取决于线粒体的变化，该变化参与了认为对细胞凋亡过程中MOMP至关重要的蛋白质，这些蛋白质最终导致不依赖caspase的坏死细胞死亡。

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