Volume 29, No 11, Nov 2019
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 29 Issue 11, November 2019: 942-952
ORIGINAL ARTICLES
BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis
Kai Huang 1,2, Katelyn L. O’Neill1, Jian Li 1,2, Wei Zhou 1,3, Na Han 1,4, Xiaming Pang1, Wei Wu 1,5, Lucas Struble1, Gloria Borgstahl1,Zhaorui Liu 1,6, Liqiang Zhang1 and Xu Luo 1,2
1 Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA; 2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198-7696, USA; 3Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060 Hubei, China; 4Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450014 Henan, China; 5Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060 Hubei, China and 6School of Medicine, Shandong University, Jinan 250012 Shandong, China
Correspondence: Xu Luo (xuluo@unmc.edu)These authors contributed equally: Kai Huang, Katelyn L. O’Neill
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.
https://doi.org/10.1038/s41422-019-0231-y
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