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首页> 外文期刊>Molecular and Cellular Biology >Pseudomonas Exotoxin A-Mediated Apoptosis Is Bak Dependent and Preceded by the Degradation of Mcl-1
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Pseudomonas Exotoxin A-Mediated Apoptosis Is Bak Dependent and Preceded by the Degradation of Mcl-1

机译：假单胞菌外毒素A介导的细胞凋亡是Bak依赖的，并且先于Mcl-1降解。

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Pseudomonas exotoxin A (PE) is a bacterial toxin that arrests protein synthesis and induces apoptosis. Here, we utilized mouse embryo fibroblasts (MEFs) deficient in Bak and Bax to determine the roles of these proteins in cell death induced by PE. PE induced a rapid and dose-dependent induction of apoptosis in wild-type (WT) and Bax knockout (Bax?/?) MEFs but failed in Bak knockout (Bak?/?) and Bax/Bak double-knockout (DKO) MEFs. Also a loss of mitochondrial membrane potential was observed in WT and Bax?/? MEFs, but not in Bak?/? or in DKO MEFs, indicating an effect of PE on mitochondrial permeability. PE-mediated inhibition of protein synthesis was identical in all 4 cell lines, indicating that differences in killing were due to steps after the ADP-ribosylation of EF2. Mcl-1, but not Bcl-xL, was rapidly degraded after PE treatment, consistent with a role for Mcl-1 in the PE death pathway. Bak was associated with Mcl-1 and Bcl-xL in MEFs and uncoupled from suppressed complexes after PE treatment. Overexpression of Mcl-1 and Bcl-xL inhibited PE-induced MEF death. Our data suggest that Bak is the preferential mediator of PE-mediated apoptosis and that the rapid degradation of Mcl-1 unleashes Bak to activate apoptosis.
机译：假单胞菌外毒素A（PE）是一种细菌毒素，可阻止蛋白质合成并诱导细胞凋亡。在这里，我们利用缺乏Bak和Bax的小鼠胚胎成纤维细胞（MEF）来确定这些蛋白质在PE诱导的细胞死亡中的作用。 PE在野生型（WT）和Bax敲除（Bax ？/？）MEF中诱导凋亡的快速和剂量依赖性诱导，但在Bak敲除（Bak ？/？ sup>）和Bax / Bak双敲除（DKO）MEF。在WT和Bax ？/？ MEF中也观察到线粒体膜电位的损失，但在Bak ？/？或DKO MEF中没有观察到，表明PE对线粒体通透性。 PE介导的蛋白质合成抑制作用在所有4种细胞系中均相同，这表明杀伤差异是由于EF2的ADP-核糖基化后的步骤所致。 PE处理后，Mcl-1而非Bcl-x L 迅速降解，这与Mcl-1在PE死亡途径中的作用一致。 Bak与MEFs中的Mcl-1和Bcl-x L 有关，并且与PE处理后的抑制复合物无关。 Mcl-1和Bcl-x L 的过表达抑制PE诱导的MEF死亡。我们的数据表明Bak是PE介导的细胞凋亡的优先介体，而Mcl-1的快速降解释放了Bak来激活细胞凋亡。

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