BAX requires VDAC2 to mediate apoptosis and to limit tumor development

Chin, H. S.; van Delft, M. F.; Ninnis, R. L.; Mark, L. X.; Tan, I. K.; Reljic, B.; Scicluna, K.; Dagley, L. F.; Sandow, J. J.; Kelly, G. L.; Chappaz, S.; Khaw, S. L.; Chang, C.; Webb, A.; Hockings, C.; Hall, C.; Kueh, A.; Ryan, M. T.; Kluck, R. M.; Bouillet, P.; Herold, M. J.; Gray, D. H.; Huang, D. C.; Dewson, G.

doi:10.1101/266668

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bioRxiv · 10.1101/266668

BAX requires VDAC2 to mediate apoptosis and to limit tumor development

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Abstract

Intrinsic apoptosis is critical for normal physiology including the prevention of tumor formation. BAX and BAK are essential for mediating this process and for the cytotoxic action of many anticancer drugs. BAX and BAK are thought to act in a functionally redundant manner and are considered to be regulated similarly. From an unbiased genome-wide CRISPR/Cas9 screen, we identified VDAC2 (voltage-dependent anion channel 2) as essential for BAX, but not BAK, to function. The genetic deletion of VDAC2 abrogated the association of BAX and BAK with mitochondrial complexes that contain VDAC1, VDAC2 and VDAC3. By disrupting its localization to mitochondria, BAX is rendered completely ineffective. Moreover, we defined an interface unique to VDAC2 that is required to drive BAX activity. Consequently, interfering with this interaction or deleting VDAC2 phenocopied the loss of BAX, including impairing the killing of tumor cells by anti-cancer agents such as the BCL-2 inhibitor venetoclax. Furthermore, the ability of BAX to prevent tumor formation was attenuated in the absence of VDAC2. Taken together, our studies show for the first time that BAX-mediated apoptosis, but not BAK-mediated apoptosis, is critically dependent on VDAC2, hence revealing the differential regulation of BAX and BAK.

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Chin, H. S., van Delft, M. F., Ninnis, R. L., Mark, L. X., Tan, I. K., Reljic, B., Scicluna, K., Dagley, L. F., Sandow, J. J., Kelly, G. L., Chappaz, S., Khaw, S. L., Chang, C., Webb, A., Hockings, C., Hall, C., Kueh, A., Ryan, M. T., Kluck, R. M., Bouillet, P., Herold, M. J., Gray, D. H., Huang, D. C., Dewson, G.. 2018-02-16. BAX requires VDAC2 to mediate apoptosis and to limit tumor development. https://doi.org/10.1101/266668

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