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VDAC2 enables BAX to mediate apoptosis and limit tumor development

Author

Listed:
  • Hui San Chin

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Mark X. Li

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Iris K. L. Tan

    (Walter and Eliza Hall Institute of Medical Research)

  • Robert L. Ninnis

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Boris Reljic

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kristen Scicluna

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Laura F. Dagley

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Jarrod J. Sandow

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Gemma L. Kelly

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Andre L. Samson

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Stephane Chappaz

    (Monash University)

  • Seong L. Khaw

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Catherine Chang

    (Walter and Eliza Hall Institute of Medical Research)

  • Andrew Morokoff

    (The University of Melbourne
    Royal Melbourne Hospital)

  • Kerstin Brinkmann

    (Walter and Eliza Hall Institute of Medical Research)

  • Andrew Webb

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • 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
    University of Melbourne)

  • Philippe Bouillet

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Marco J. Herold

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Daniel H. D. Gray

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • David C. S. Huang

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Mark F. Delft

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Grant Dewson

    (Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

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.

Suggested Citation

  • 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. Kh, 2018. "VDAC2 enables BAX to mediate apoptosis and limit tumor development," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07309-4
    DOI: 10.1038/s41467-018-07309-4
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