VDAC2 Enables BAX to Mediate Apoptosis and Limit Tumor Development

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Nov 28

PMID 30478310

Citations 88

Authors

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 van Delft

Grant Dewson

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Anderson M, Deng J, Seymour J, Tam C, Kim S, Fein J . The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood. 2016; 127(25):3215-24. PMC: 4920022. DOI: 10.1182/blood-2016-01-688796. View

Roberts A, Davids M, Pagel J, Kahl B, Puvvada S, Gerecitano J . Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2015; 374(4):311-22. PMC: 7107002. DOI: 10.1056/NEJMoa1513257. View

Sarosiek K, Chi X, Bachman J, Sims J, Montero J, Patel L . BID preferentially activates BAK while BIM preferentially activates BAX, affecting chemotherapy response. Mol Cell. 2013; 51(6):751-65. PMC: 4164233. DOI: 10.1016/j.molcel.2013.08.048. View

Souers A, Leverson J, Boghaert E, Ackler S, Catron N, Chen J . ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013; 19(2):202-8. DOI: 10.1038/nm.3048. View

Baines C, Kaiser R, Sheiko T, Craigen W, Molkentin J . Voltage-dependent anion channels are dispensable for mitochondrial-dependent cell death. Nat Cell Biol. 2007; 9(5):550-5. PMC: 2680246. DOI: 10.1038/ncb1575. View

Anflous K, Armstrong D, Craigen W . Altered mitochondrial sensitivity for ADP and maintenance of creatine-stimulated respiration in oxidative striated muscles from VDAC1-deficient mice. J Biol Chem. 2000; 276(3):1954-60. DOI: 10.1074/jbc.M006587200. View

Iyer S, Anwari K, Alsop A, Yuen W, Huang D, Carroll J . Identification of an activation site in Bak and mitochondrial Bax triggered by antibodies. Nat Commun. 2016; 7:11734. PMC: 4890306. DOI: 10.1038/ncomms11734. View

Shimizu S, Narita M, Tsujimoto Y . Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature. 1999; 399(6735):483-7. DOI: 10.1038/20959. View

LINDSTEN T, Ross A, King A, Zong W, Rathmell J, Shiels H . The combined functions of proapoptotic Bcl-2 family members bak and bax are essential for normal development of multiple tissues. Mol Cell. 2001; 6(6):1389-99. PMC: 3057227. DOI: 10.1016/s1097-2765(00)00136-2. View

10.

Willis S, Fletcher J, Kaufmann T, van Delft M, Chen L, Czabotar P . Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science. 2007; 315(5813):856-9. DOI: 10.1126/science.1133289. View

11.

Ran F, Hsu P, Wright J, Agarwala V, Scott D, Zhang F . Genome engineering using the CRISPR-Cas9 system. Nat Protoc. 2013; 8(11):2281-2308. PMC: 3969860. DOI: 10.1038/nprot.2013.143. View

12.

Knudson C, Tung K, Tourtellotte W, Brown G, Korsmeyer S . Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science. 1995; 270(5233):96-9. DOI: 10.1126/science.270.5233.96. View

13.

Patel A, Lauritzen I, Lazdunski M, Honore E . Disruption of mitochondrial respiration inhibits volume-regulated anion channels and provokes neuronal cell swelling. J Neurosci. 1998; 18(9):3117-23. PMC: 6792668. View

14.

Czabotar P, Lessene G, Strasser A, Adams J . Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat Rev Mol Cell Biol. 2013; 15(1):49-63. DOI: 10.1038/nrm3722. View

15.

Kueh A, Pal M, Tai L, Liao Y, Smyth G, Shi W . An update on using CRISPR/Cas9 in the one-cell stage mouse embryo for generating complex mutant alleles. Cell Death Differ. 2017; 24(10):1821-1822. PMC: 5596424. DOI: 10.1038/cdd.2017.122. View

16.

Sampson M, Decker W, Beaudet A, Ruitenbeek W, Armstrong D, Hicks M . Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3. J Biol Chem. 2001; 276(42):39206-12. DOI: 10.1074/jbc.M104724200. View

17.

Leverson J, Phillips D, Mitten M, Boghaert E, Diaz D, Tahir S . Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med. 2015; 7(279):279ra40. DOI: 10.1126/scitranslmed.aaa4642. View

18.

Tse C, Shoemaker A, Adickes J, Anderson M, Chen J, Jin S . ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res. 2008; 68(9):3421-8. DOI: 10.1158/0008-5472.CAN-07-5836. View

19.

Gallenne T, Gautier F, Oliver L, Hervouet E, Noel B, Hickman J . Bax activation by the BH3-only protein Puma promotes cell dependence on antiapoptotic Bcl-2 family members. J Cell Biol. 2009; 185(2):279-90. PMC: 2700382. DOI: 10.1083/jcb.200809153. View

20.

Wei M, Zong W, Cheng E, LINDSTEN T, Panoutsakopoulou V, Ross A . Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science. 2001; 292(5517):727-30. PMC: 3049805. DOI: 10.1126/science.1059108. View