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

Katelyn L. O’neill, Kai Huang, Jingjing Zhang, Yi Chen, Xu Luo

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

The mechanism of Bax/Bak activation remains a central question in mitochondria-dependent apoptotic signaling. While it is established that all proapoptotic Bcl-2 homology 3 (BH3)-only proteins bind and neutralize the anti-apoptotic Bcl-2 family proteins, how this neutralization leads to Bax/Bak activation has been actively debated. Here, genome editing was used to generate cells deficient for all eight proapoptotic BH3-only proteins (OctaKO) and those that lack the entire Bcl-2 family (Bcl-2 allKO). Although the OctaKO cells were resistant to most apoptotic stimuli tested, they underwent Bax/Bak-dependent and p53/Rb-independent apoptosis efficiently when both Bcl-xL and Mcl-1, two anti-apoptotic Bcl-2 proteins, were inactivated or eliminated. Strikingly, when expressed in the Bcl-2 allKO cells, both Bax and Bak spontaneously associated with the outer mitochondrial membrane (OMM) through their respective helix 9, and this association triggered their homo-oligomerization/activation. Together, these results strongly suggest that the OMM, not BH3-only proteins or p53/Rb, is the long-sought-after direct activator of Bax/Bak following BH3-only-mediated neutralization of anti-apoptotic Bcl-2 proteins.

Original languageEnglish (US)
Pages (from-to)973-988
Number of pages16
JournalGenes and Development
Volume30
Issue number8
DOIs
StatePublished - Apr 15 2016

Keywords

  • Anti-apoptotic Bcl-2 proteins
  • BH3-only
  • Bax/Bak activation
  • Outer mitochondrial membrane

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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