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

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Abstract

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
Volume29
Issue number11
DOIs
StatePublished - Nov 1 2019

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Apoptosis
Proteins
Membranes
Mitochondrial Membranes
Mitochondria
Ligands

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Huang, K., O’Neill, K. L., Li, J., Zhou, W., Han, N., Pang, X., ... Luo, X. (2019). BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis. Cell Research, 29(11), 942-952. https://doi.org/10.1038/s41422-019-0231-y

BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis. / Huang, Kai; O’Neill, Katelyn L.; Li, Jian; Zhou, Wei; Han, Na; Pang, Xiaming; Wu, Wei; Struble, Lucas; Borgstahl, Gloria; Liu, Zhaorui; Zhang, Liqiang; Luo, Xu.

In: Cell Research, Vol. 29, No. 11, 01.11.2019, p. 942-952.

Research output: Contribution to journalArticle

Huang, K, O’Neill, KL, Li, J, Zhou, W, Han, N, Pang, X, Wu, W, Struble, L, Borgstahl, G, Liu, Z, Zhang, L & Luo, X 2019, 'BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis', Cell Research, vol. 29, no. 11, pp. 942-952. https://doi.org/10.1038/s41422-019-0231-y
Huang K, O’Neill KL, Li J, Zhou W, Han N, Pang X et al. BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis. Cell Research. 2019 Nov 1;29(11):942-952. https://doi.org/10.1038/s41422-019-0231-y
Huang, Kai ; O’Neill, Katelyn L. ; Li, Jian ; Zhou, Wei ; Han, Na ; Pang, Xiaming ; Wu, Wei ; Struble, Lucas ; Borgstahl, Gloria ; Liu, Zhaorui ; Zhang, Liqiang ; Luo, Xu. / BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis. In: Cell Research. 2019 ; Vol. 29, No. 11. pp. 942-952.
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AU - Han, Na

AU - Pang, Xiaming

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