Inactivation of prosurvival Bcl-2 proteins activates Bax/Bak through the outer mitochondrial membrane
Open accessAbstract
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.
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Some BH3-only proteins including BAD, BMF, or HRK promote MOMP in the absence of a physical interaction with BAX or BAK.
“Importantly, some BH3-only proteins including BCL2 associated agonist of cell death (BAD), Bcl2 modifying factor (BMF), or harakiri, BCL2 interacting protein (HRK) promote MOMP in the absence of a physical interaction with BAX or BAK.”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [93]
These BH3-only proteins (sensitizers or inactivators) bind to anti-apoptotic BCL2 family members and hence limit their availability to sequester BAX, BAK, or BH3-only activators.
“These BH3-only proteins, which are sometimes referred to as “sensitizers” or “inactivators” bind to anti-apoptotic BCL2 family members and hence limit their availability to sequester BAX, BAK, or BH3-only activators [58, 93].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [93]
BAX and BAK can self-activate in the absence of anti-apoptotic BCL2 family members and pro-apoptotic BH3 proteins (according to a relatively slow kinetics).
“This observation is in line with the notion that BAX and BAK can self-activate in the absence of anti-apoptotic BCL2 family members and pro-apoptotic BH3 proteins (according to a relatively slow kinetics) [64, 93].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [93]
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- Authors
- O'Neill, K. L., Huang, K., Zhang, J., Chen, Y., & Luo, X.
- Affiliations
- Fred and Pamela Buffett Cancer Center (US)
- Central South University (CN)
- Corresponding author
- Luo, Xu
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2016-04-07
- Volume
- 30
- Issue
- 8
- Pages
- 973-988
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC4840302
- OpenAlex
- W2329205123
- Cited by
- 323
- References
- 63
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 37 · 2023: 28 · 2022: 35 · 2021: 42 · 2020: 40 · 2019: 29 · 2018: 30 · 2017: 30 · 2016: 15
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Nebraska Center for Cellular Signaling (P20-GM103489)
- Nebraska Research Initiative Funds
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Bax activation, Bak activation, Bcl-2 family proteins, BH3-only proteins, mitochondrial outer membrane, mitochondrial apoptosis, Bcl-xL, Mcl-1, p53-independent apoptosis
- MeSH terms
- Animals, Cell Line, Gene Expression Regulation, HeLa Cells, Humans, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Gene Silencing, HCT116 Cells, bcl-2 Homologous Antagonist-Killer Protein, bcl-2-Associated X Protein, Mitochondrial Membranes, Mice, Myeloid Cell Leukemia Sequence 1 Protein
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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