VDAC2 enables BAX to mediate apoptosis and limit tumor development

Hui San Chin, Mark X. Li, Iris K. L. Tan, Robert L. Ninnis, Boris Reljic, Kristen Scicluna, Laura F. Dagley, Jarrod J. Sandow, Gemma L. Kelly, Andre L. Samson, Stephane Chappaz, Seong L. Khaw, Catherine Chang, Andrew Morokoff, Kerstin Brinkmann, Andrew Webb, Colin Hockings, Cathrine M. Hall, Andrew J. Kueh, Michael T. Ryan, Ruth M. Kluck, Philippe Bouillet, Marco J. Herold, Daniel H. D. Gray, David C. S. Huang, Mark F. Delft () and Grant Dewson ()
Additional contact information
Hui San Chin: Walter and Eliza Hall Institute of Medical Research
Mark X. Li: Walter and Eliza Hall Institute of Medical Research
Iris K. L. Tan: Walter and Eliza Hall Institute of Medical Research
Robert L. Ninnis: Walter and Eliza Hall Institute of Medical Research
Boris Reljic: Walter and Eliza Hall Institute of Medical Research
Kristen Scicluna: Walter and Eliza Hall Institute of Medical Research
Laura F. Dagley: Walter and Eliza Hall Institute of Medical Research
Jarrod J. Sandow: Walter and Eliza Hall Institute of Medical Research
Gemma L. Kelly: Walter and Eliza Hall Institute of Medical Research
Andre L. Samson: Walter and Eliza Hall Institute of Medical Research
Stephane Chappaz: Monash University
Seong L. Khaw: Walter and Eliza Hall Institute of Medical Research
Catherine Chang: Walter and Eliza Hall Institute of Medical Research
Andrew Morokoff: The University of Melbourne
Kerstin Brinkmann: Walter and Eliza Hall Institute of Medical Research
Andrew Webb: Walter and Eliza Hall Institute of Medical Research
Colin Hockings: Walter and Eliza Hall Institute of Medical Research
Cathrine M. Hall: Walter and Eliza Hall Institute of Medical Research
Andrew J. Kueh: Walter and Eliza Hall Institute of Medical Research
Michael T. Ryan: Monash University
Ruth M. Kluck: Walter and Eliza Hall Institute of Medical Research
Philippe Bouillet: Walter and Eliza Hall Institute of Medical Research
Marco J. Herold: Walter and Eliza Hall Institute of Medical Research
Daniel H. D. Gray: Walter and Eliza Hall Institute of Medical Research
David C. S. Huang: Walter and Eliza Hall Institute of Medical Research
Mark F. Delft: Walter and Eliza Hall Institute of Medical Research
Grant Dewson: Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract Intrinsic apoptosis is critical to prevent tumor formation and is engaged by many anti-cancer agents to eliminate tumor cells. BAX and BAK, the two essential mediators of apoptosis, are thought to be regulated through similar mechanisms and act redundantly to drive apoptotic cell death. From an unbiased genome-wide CRISPR/Cas9 screen, we identified VDAC2 (voltage-dependent anion channel 2) as important for BAX, but not BAK, to function. Genetic deletion of VDAC2 abrogated the association of BAX and BAK with mitochondrial complexes containing VDAC1, VDAC2, and VDAC3, but only inhibited BAX apoptotic function. Deleting VDAC2 phenocopied the loss of BAX in impairing both the killing of tumor cells by anti-cancer agents and the ability to suppress tumor formation. Together, our studies show that efficient BAX-mediated apoptosis depends on VDAC2, and reveal a striking difference in how BAX and BAK are functionally impacted by their interactions with VDAC2.

Date: 2018
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DOI: 10.1038/s41467-018-07309-4

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