Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies

Kim, Hyungjin; Rafiuddin-Shah, Mubina; Tu, Ho-Chou; Jeffers, John R.; Zambetti, Gerard P.; Hsieh, James J.-D.; Cheng, Emily H.-Y.

doi:10.1038/ncb1499

Cited by 874Cell death mechanisms and regulationMitochondrial Function and PathologyCancer-related Molecular Pathways

Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies

Kim, Hyungjin, Rafiuddin-Shah, Mubina, Tu, Ho-Chou, Jeffers, John R., Zambetti, Gerard P., Hsieh, James J.-D., Cheng, Emily H.-Y.·2006·Nature Cell Biology

DOI 10.1038/ncb1499

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Abstract

Although the BCL-2 family constitutes a crucial checkpoint in apoptosis, the intricate interplay between these family members remains elusive. Here, we demonstrate that BIM and PUMA, similar to truncated BID (tBID), directly activate BAX-BAK to release cytochrome c. Conversely, anti-apoptotic BCL-2-BCL-X(L)-MCL-1 sequesters these 'activator' BH3-only molecules into stable complexes, thus preventing the activation of BAX-BAK. Extensive mutagenesis of BAX-BAK indicates that their activity is not kept in check by BCL-2-BCL-X(L)-MCL-1. Anti-apoptotic BCL-2 members are differentially inactivated by the remaining 'inactivator' BH3-only molecules including BAD, NOXA, BMF, BIK/BLK and HRK/DP5. BAD displaces tBID, BIM or PUMA from BCL-2-BCL-X(L) to activate BAX-BAK, whereas NOXA specifically antagonizes MCL-1. Coexpression of BAD and NOXA killed wild-type but not Bax, Bak doubly deficient cells or Puma deficient cells with Bim knockdown, indicating that activator BH3-only molecules function downstream of inactivator BH3-only molecules to activate BAX-BAK. Our data establish a hierarchical regulation of mitochondrion-dependent apoptosis by various BCL-2 subfamilies.

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Upon induction of apoptosis, BAX retrotranslocation ceases as the mitochondrial pools of BAX and BAK undergo direct or indirect activation by pro-apoptotic BH3-only proteins.
“Upon induction of apoptosis, BAX retrotranslocation ceases as the mitochondrial pools of BAX and BAK undergo direct or indirect activation (see below) by pro-apoptotic BH3-only proteins [48, 56–59].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [59]
BID, BIM, PUMA, and NOXA share the ability to physically interact with the mitochondrial pool of BAX and/or BAK to promote conformational changes culminating with dissociation of the core and latch domains of BCL2 effectors.
“BID, BIM, PUMA, and NOXA share the ability to physically (but transiently) interact with the mitochondrial pool of BAX and/or BAK (hence being known as “activators”) to promote a series of conformational changes [59, 64, 67, 71–74] culminating with the dissociation of the core and latch domains of BCL2 effectors [75–77].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [59]

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Authors: Kim, H., Rafiuddin-Shah, M., Tu, H.-C., Jeffers, J. R., Zambetti, G. P., Hsieh, J. J.-D., & Cheng, E. H.-Y.
Affiliations: Washington University in St. Louis (US)
St. Jude Children's Research Hospital (US)
Corresponding author: Cheng, Emily H.-Y.
ORCID: Kim, Hyungjin
Tu, Ho-Chou
Zambetti, Gerard P.
Hsieh, James J.-D.
Cheng, Emily H.-Y.
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2006-11-19
Volume: 8
Issue: 12
Pages: 1348-1358
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/ncb1499
OpenAlex: W2008376982
Cited by: 874
References: 51
Citations by year: 2026: 9 · 2025: 16 · 2024: 13 · 2023: 24 · 2022: 25 · 2021: 27 · 2020: 21 · 2019: 25 · 2018: 31 · 2017: 33 · 2016: 38 · 2015: 56 · 2014: 45 · 2013: 58 · 2012: 51
FWCI: 33.68
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Cell Biology (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (R01CA063230, CA-63230)
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 › Oncology › Cancer-related Molecular Pathways
Keywords: Bcl-2 family proteins, mitochondrial apoptosis, BH3-only proteins, building information modeling, PUMA, Bad, Noxa, Mcl-1, Bcl-xL, Bcl-2, Bid, cytochrome c release, hierarchical regulation, anti-apoptotic proteins
MeSH terms: Bcl-2-Like Protein 11, Animals, Membrane Proteins, Mitochondria, Neoplasm Proteins, Proto-Oncogene Proteins, Apoptosis, Proto-Oncogene Proteins c-bcl-2, Tumor Suppressor Proteins, Cytochromes c, bcl-2 Homologous Antagonist-Killer Protein, Apoptosis Regulatory Proteins, bcl-X Protein, BH3 Interacting Domain Death Agonist Protein, bcl-2-Associated X Protein, Mice, Myeloid Cell Leukemia Sequence 1 Protein

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Hierarchical regulation of mitochondrion-dependent apoptosis by BCL-2 subfamilies

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