Mito-priming as a method to engineer Bcl-2 addiction

Jonathan Lopez, Margaux Bessou, Joel S. Riley, Evangelos Giampazolias, Franziska Todt, Tony Rochegüe, Andrew Oberst, Douglas R. Green, Frank Edlich, Gabriel Ichim and Stephen W. G. Tait ()
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Jonathan Lopez: Cancer Research UK Beatson Institute
Margaux Bessou: Cancer Research UK Beatson Institute
Joel S. Riley: Cancer Research UK Beatson Institute
Evangelos Giampazolias: Cancer Research UK Beatson Institute
Franziska Todt: Institute for Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg
Tony Rochegüe: Cancer Research UK Beatson Institute
Andrew Oberst: University of Washington
Douglas R. Green: St Jude Children’s Research Hospital
Frank Edlich: Institute for Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg
Gabriel Ichim: Cancer Research UK Beatson Institute
Stephen W. G. Tait: Cancer Research UK Beatson Institute

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms10538

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