BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis.
Apoptosis
/ physiology
BH3 Interacting Domain Death Agonist Protein
/ physiology
Bcl-2-Like Protein 11
/ physiology
HCT116 Cells
HEK293 Cells
Humans
Mitochondria
/ metabolism
Mitochondrial Membranes
/ metabolism
Myeloid Cell Leukemia Sequence 1 Protein
/ metabolism
Proto-Oncogene Proteins c-bcl-2
/ metabolism
bcl-2 Homologous Antagonist-Killer Protein
/ metabolism
bcl-X Protein
/ metabolism
Journal
Cell research
ISSN: 1748-7838
Titre abrégé: Cell Res
Pays: England
ID NLM: 9425763
Informations de publication
Date de publication:
Nov 2019
Nov 2019
Historique:
received:
30
01
2019
accepted:
30
08
2019
pubmed:
26
9
2019
medline:
9
9
2020
entrez:
26
9
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31551537
doi: 10.1038/s41422-019-0231-y
pii: 10.1038/s41422-019-0231-y
pmc: PMC6888900
doi:
Substances chimiques
BAK1 protein, human
0
BCL2 protein, human
0
BCL2L1 protein, human
0
BH3 Interacting Domain Death Agonist Protein
0
BID protein, human
0
Bcl-2-Like Protein 11
0
MCL1 protein, human
0
Myeloid Cell Leukemia Sequence 1 Protein
0
Proto-Oncogene Proteins c-bcl-2
0
bcl-2 Homologous Antagonist-Killer Protein
0
bcl-X Protein
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
942-952Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM118437
Pays : United States
Organisme : NCI NIH HHS
ID : R03 CA205496
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : 5R01GM118437
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : 5R03CA205496
Organisme : NIGMS NIH HHS
ID : R01 GM076237
Pays : United States
Organisme : NCRR NIH HHS
ID : P20 RR018759
Pays : United States
Commentaires et corrections
Type : CommentIn
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