BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis

Kai Huang, Katelyn L. O’Neill, Jian Li, Wei Zhou, Na Han, Xiaming Pang, Wei Wu, Lucas Struble, Gloria Borgstahl, Zhaorui Liu, Liqiang Zhang, Xu Luo

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


It has been widely accepted that mitochondria-dependent apoptosis initiates when select BH3-only proteins (BID, BIM, etc.) directly engage and allosterically activate effector proteins BAX/BAK. Here, through reconstitution of cells lacking all eight pro-apoptotic BH3-only proteins, we demonstrate that all BH3-only proteins primarily target the anti-apoptotic BCL-2 proteins BCL-xL/MCL-1, whose simultaneous suppression enables membrane-mediated spontaneous activation of BAX/BAK. BH3-only proteins’ apoptotic activities correlate with affinities for BCL-xL/MCL-1 instead of abilities to directly activate BAX/BAK. Further, BID and BIM do not distinguish BAX from BAK or accelerate BAX/BAK activation following inactivation of BCL-xL/MCL-1. Remarkably, death ligand-induced apoptosis in cells lacking BH3-only proteins and MCL-1 is fully restored by BID mutants capable of neutralizing BCL-xL, but not direct activation of BAX/BAK. Taken together, our findings provide a “Membrane-mediated Permissive” model, in which the BH3-only proteins only indirectly activate BAX/BAK by neutralizing the anti-apoptotic BCL-2 proteins, and thus allowing BAX/BAK to undergo unimpeded, spontaneous activation in the mitochondrial outer membrane milieu, leading to apoptosis initiation.

Original languageEnglish (US)
Pages (from-to)942-952
Number of pages11
JournalCell Research
Issue number11
StatePublished - Nov 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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