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Cell Death Dis. 2018 Apr 1;9(4):430. doi: 10.1038/s41419-018-0464-6.

Bax retrotranslocation potentiates Bcl-xL's antiapoptotic activity and is essential for switch-like transitions between MOMP competency and resistance.

Author information

1
Department of Biology, Chair of Biochemical Pharmacology, University of Konstanz, 78457, Konstanz, Germany.
2
Konstanz Research School Chemical Biology, University of Konstanz, 78457, Konstanz, Germany.
3
Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, Hoppe-Seyler-Str. 4, 72076, Tübingen, Germany.
4
Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. markus.morrison@izi.uni-stuttgart.de.
5
Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland. markus.morrison@izi.uni-stuttgart.de.
6
Institute of Cell Biology and Immunology, University of Stuttgart, 70569, Stuttgart, Germany. markus.morrison@izi.uni-stuttgart.de.
7
Stuttgart Research Center Systems Biology, University of Stuttgart, 70569, Stuttgart, Germany. markus.morrison@izi.uni-stuttgart.de.

Abstract

The rapid, typically all-or-none process of mitochondrial outer membrane permeabilization (MOMP) constitutes a primary cell death decision that is controlled by the Bcl-2 family interactome. However, how strict all-or-none MOMP decisions are governed by and emanate from the dynamic interplay of pro- and antiapoptotic Bcl-2 family members remains incompletely understood. In particular, it is unclear to which extent the shuttling of Bcl-2 family species between lipid and aqueous phases contributes to regulating MOMP sensitivity. Here, we studied the interplay of tBid, Bax, and Bcl-xL, using a combined approach of deterministic mathematical modeling and retrospective as well as prospective experimental testing of model predictions. Systems modeling of the tBid-Bax interplay and their fluxes between cytosol and mitochondrial membranes reproduced experimental data on tBid-triggered Bax activation and oligomerization highly accurately. Extending these studies to analyze the cell-protective role of Bcl-xL strikingly revealed that the activity of Bcl-xL to retrotranslocate activated Bax from membranes back into the cytosol is essential to reproduce or correctly predict experimental outcomes. These included the potency of Bcl-xL in suppressing Bax oligomerization, its role in limiting Bax membrane recruitment, the resistance threshold to low concentrations of MOMP triggers as well as a response potentiaton arising from combinations of tBid and sensitizer BH3-only peptides. Importantly, retrotranslocation activity of Bcl-xL is necessary to strictly separate conditions of MOMP competency and resistance. Our results therefore identify Bax retrotranslocation by Bcl-xL as an indispensable component of the molecular switch by which Bcl-2 family members govern cellular death decisions.

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