BH3-only proteins target BCL-xL/MCL-1, not BAX/BAK, to initiate apoptosis

Cell Res. 2019 Nov;29(11):942-952. doi: 10.1038/s41422-019-0231-y.

Kai Huang ^# ¹ ², Katelyn L O'Neill ^# ¹, Jian Li ¹ ², Wei Zhou ¹ ³, Na Han ¹ ⁴, Xiaming Pang ¹, Wei Wu ¹ ⁵, Lucas Struble ¹, Gloria Borgstahl ¹, Zhaorui Liu ¹ ⁶, Liqiang Zhang ¹, Xu Luo ⁷ ⁸

Affiliations

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.
2 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-7696, USA.
3 Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
4 Department of Oncology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, Henan, China.
5 Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
6 School of Medicine, Shandong University, Jinan, 250012, Shandong, China.
7 Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-7696, USA. [email protected].
8 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198-7696, USA. [email protected].
# Contributed equally.

PMID: 31551537 DOI: 10.1038/s41422-019-0231-y

Abstract

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.

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