TY - JOUR
T1 - BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis
AU - Huang, Kai
AU - O’Neill, Katelyn L.
AU - Li, Jian
AU - Zhou, Wei
AU - Han, Na
AU - Pang, Xiaming
AU - Wu, Wei
AU - Struble, Lucas
AU - Borgstahl, Gloria
AU - Liu, Zhaorui
AU - Zhang, Liqiang
AU - Luo, Xu
N1 - Publisher Copyright:
© 2019, IBCB, SIBS, CAS.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85073945686&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073945686&partnerID=8YFLogxK
U2 - 10.1038/s41422-019-0231-y
DO - 10.1038/s41422-019-0231-y
M3 - Article
C2 - 31551537
AN - SCOPUS:85073945686
SN - 1001-0602
VL - 29
SP - 942
EP - 952
JO - Cell Research
JF - Cell Research
IS - 11
ER -