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VDAC2 enables BAX to mediate apoptosis and limit tumor development

Published Date: 2019-06-20      Source: http://www.unitedwellhk.com/index.php/news/detail/id/118.html


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.

 

Introduction


Apoptotic  death is a fundamental process that is essential for embryonic development and immune system homeostasis. BAX and BAK are members of the BCL-2 family of proteins that have essential, but redundant, functions as mediators of intrinsic apoptosis. The activation of BAX and BAK and their consequent self-association permeabilizes the mitochondrial outer membrane (MOM) to instigate cytochrome c release and  death. While BAK is predominantly integrated into the MOM, BAX is predominantly cytosolic. Their distinct subcellular localizations may reflect different rates of retrotranslocation from the MOM to the cytosol, although the precise determinants of their recruitment to the MOM to mediate  killing are unclear. Many chemotherapeutic agents indirectly trigger BAX/BAK-mediated apoptosis whereas BH3-mimetic compounds, such as venetoclax (ABT-199), directly inhibit BCL-2 proteins to drive apoptosis. Venetoclax, which selectively targets BCL-2, has proven highly efficacious for patients with high-risk chronic lymphocytic leukemia (CLL) leading to its approval for treating such patients.


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The VDAC channels (VDAC1, VDAC2, and VDAC3) are responsible for the transport of low molecular weight metabolites across the MOM including adenosine triphosphate (ATP) and adenosine diphosphate (ADP). Early studies suggested that the VDACs were responsible for the release of cytochrome c across the MOM. However, that cells devoid of all three VDAC isoforms could still undergo apoptosis argued against such a role. Instead, VDACs have been proposed to influence apoptosis by interacting with BCL-2 family proteins including BCL-XL, BAX, and BAK. In this regard, the prevailing dogma is that VDAC2 acts to limit apoptosis by sequestering BAK.


In marked contrast to this, we identified VDAC2 in an unbiased genome-wide screen for factors required for BAX to function. In the absence of VDAC2, cell killing mediated by BAX, but not BAK, is abolished. Moreover, the interaction with VDAC2 is critical for BAX to mediate cell death in response to chemotherapeutic agents both in vitro and in vivo, as well as for BAX to limit tumor development in a cMyc-driven model of acute myeloid leukemia (AML). Our genetic and functional studies unequivocally define a critical and unique requirement for VDAC2 in the apoptotic activity of BAX.

 

Source:Nat Commun:揭示调节细胞凋亡的一种新组分---蛋白VDAC2

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