Mito-priming as a method to engineer Bcl-2 addiction.,Nature Communications

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Mito-priming as a method to engineer Bcl-2 addiction.
Nature Communications ( IF 14.7 ) Pub Date : 2016-Feb-02 , DOI: 10.1038/ncomms10538
Jonathan Lopez _{1,

2} , Margaux Bessou _{1,

2} , Joel S Riley _{1,

2} , Evangelos Giampazolias _{1,

2} , Franziska Todt ₃ , Tony Rochegüe _{1,

2} , Andrew Oberst ₄ , Douglas R Green ₅ , Frank Edlich _{3,

6} , Gabriel Ichim _{1,

2} , Stephen W G Tait _{1,

2}

Affiliation

Most apoptotic stimuli require mitochondrial outer membrane permeabilization (MOMP) in order to execute cell death. As such, MOMP is subject to tight control by Bcl-2 family proteins. We have developed a powerful new technique to investigate Bcl-2-mediated regulation of MOMP. This method, called mito-priming, uses co-expression of pro- and anti-apoptotic Bcl-2 proteins to engineer Bcl-2 addiction. On addition of Bcl-2 targeting BH3 mimetics, mito-primed cells undergo apoptosis in a rapid and synchronous manner. Using this method we have comprehensively surveyed the efficacy of BH3 mimetic compounds, identifying potent and specific MCL-1 inhibitors. Furthermore, by combining different pro- and anti-apoptotic Bcl-2 pairings together with CRISPR/Cas9-based genome editing, we find that tBID and PUMA can preferentially kill in a BAK-dependent manner. In summary, mito-priming represents a facile and robust means to trigger mitochondrial apoptosis.

中文翻译：

Mito-priming 作为一种设计 Bcl-2 成瘾的方法。

大多数细胞凋亡刺激需要线粒体外膜透化（MOMP）才能执行细胞死亡。因此，MOMP 受到 Bcl-2 家族蛋白的严格控制。我们开发了一种强大的新技术来研究 Bcl-2 介导的 MOMP 调节。这种方法称为 mito-priming，利用促凋亡和抗凋亡 Bcl-2 蛋白的共表达来改造 Bcl-2 成瘾。添加靶向 BH3 模拟物的 Bcl-2 后，线粒体引发的细胞会以快速、同步的方式发生凋亡。使用这种方法，我们全面调查了 BH3 模拟化合物的功效，确定了有效且特异性的 MCL-1 抑制剂。此外，通过将不同的促凋亡和抗凋亡 Bcl-2 配对与基于 CRISPR/Cas9 的基因组编辑相结合，我们发现 tBID 和 PUMA 可以以 BAK 依赖性方式优先杀死细胞。总之，线粒体引发是触发线粒体凋亡的一种简便而有效的方法。

更新日期：2016-02-05

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