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Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane

Katelyn L O'Neill1, Kai Huang1, Jingjing Zhang2

  • 1Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA;

Genes & Development
|April 9, 2016
PubMed

Insights

The outer mitochondrial membrane (OMM) directly activates Bax and Bak during apoptosis, independent of BH3-only proteins or p53/Rb. This finding clarifies a central question in programmed cell death signaling.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Mitochondria-dependent apoptosis involves proapoptotic BH3-only proteins neutralizing anti-apoptotic Bcl-2 proteins.
  • The precise mechanism by which Bax/Bak activation occurs after this neutralization is debated.

Purpose of the Study:

  • To investigate the direct activator of Bax and Bak in mitochondria-dependent apoptosis.
  • To elucidate the role of BH3-only proteins, p53/Rb, and the outer mitochondrial membrane in Bax/Bak activation.

Main Methods:

  • Utilized genome editing to create cells lacking all proapoptotic BH3-only proteins (OctaKO) and the entire Bcl-2 family (Bcl-2 allKO).
  • Assessed apoptosis induction and Bax/Bak localization and activation in engineered cell lines under various conditions.

Main Results:

  • OctaKO cells underwent Bax/Bak-dependent apoptosis when anti-apoptotic proteins Bcl-xL and Mcl-1 were absent.
  • In Bcl-2 allKO cells, Bax and Bak spontaneously associated with the outer mitochondrial membrane (OMM) via helix 9, leading to homo-oligomerization and activation.
  • This activation was independent of p53/Rb.

Conclusions:

  • The outer mitochondrial membrane (OMM) acts as the direct activator of Bax and Bak.
  • Bax/Bak activation is triggered by the OMM following the neutralization of anti-apoptotic Bcl-2 proteins by BH3-only proteins.
Keywords:
BH3-onlyBax/Bak activationanti-apoptotic Bcl-2 proteinsouter mitochondrial membrane

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