VDAC2 enables BAX to mediate apoptosis and limit tumor development

Hui San Chin; Mark X Li; Iris KL 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 HD Gray; David CS Huang; Mark F van Delft; Grant Dewson

Journal article

VDAC2 enables BAX to mediate apoptosis and limit tumor development

Hui San Chin, Mark X Li, Iris KL 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 Show all

NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2018

DOI: 10.1038/s41467-018-07309-4

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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 ce..

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University of Melbourne Researchers

Andrew Morokoff Author Surgery - Royal Melbourne Hospital

Andrew Webb Author Medical Biology (w.e.h.i.)

Kerstin Brinkmann Author Medical Biology (w.e.h.i.)

Laura Dagley Author Medical Biology (w.e.h.i.)

Philippe Bouillet Author Medical Biology (w.e.h.i.)

Grants

Awarded by Australian National Health and Medical Research Council

Awarded by Leukaemia & Lymphoma Society (SCOR grant)

Awarded by Australian Research Council

Awarded by Victorian State Government

Funding Acknowledgements

Jason Corbin for Advia blood analysis, Crystal Stilvala, Nicole Lynch and Shannon Oliver, Carmen Epifanio, Tracey Ballinger and Marina Patsis for animal husbandry, Reema Jain, Antonia Policheni and Wenxi Zhou for assistance. We thank Andreas Strasser, Benjamin Kile, James Murphy, Marc Pellegrini, and Zina Valaydon for critical comments and input, Guillaume Lessene and Jean-Marc Garnier for A1331852, and William Craigen for WT and Vdac2<SUP>-/-</SUP> MEFs. This work was supported by scholarships to HSC from Melbourne University (MIRS, MIFRS) and the Walter and Eliza Hall Institute of Medical Research (Edith Moffatt), fellowships (1043149 to DCSH and 1090236 to DHDG) and grants (1016701, 1057742, 1059290, 1078763, 1078924, 1083077, 1113133, 1124737) from the Australian National Health and Medical Research Council, a Leukaemia & Lymphoma Society (SCOR grant 7001-13), the Australian Cancer Research Foundation, a fellowship from the Australian Research Council (FT100100791 to GD), the Cancer Council Victoria (grants-in-aid to DCSH and DHDG) and operational infrastructure grants through the Australian Government IRISS and the Victorian State Government OIS 9000220.