Bax retrotranslocation potentiates Bcl-xL's antiapoptotic activity and is essential for switch-like transitions between MOMP competency and resistance.
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-xLstrikingly revealed that the activity of Bcl-xLto retrotranslocate activated Bax from membranes back into the cytosol is essential to reproduce or correctly predict experimental outcomes. These included the potency of Bcl-xLin 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-xLis necessary to strictly separate conditions of MOMP competency and resistance. Our results therefore identify Bax retrotranslocation by Bcl-xLas an indispensable component of the molecular switch by which Bcl-2 family members govern cellular death decisions.
%0 Journal Article
%1 Hantusch2018
%A Hantusch, Annika
%A Das, Kushal K
%A García-Sáez, Ana J
%A Brunner, Thomas
%A Rehm, Markus
%D 2018
%J Cell death & disease
%K 2018 izi morrison
%N 4
%P 430
%R 10.1038/s41419-018-0464-6
%T Bax retrotranslocation potentiates Bcl-xL's antiapoptotic activity and is essential for switch-like transitions between MOMP competency and resistance.
%U http://www.ncbi.nlm.nih.gov/pubmed/29567940
%V 9
%X 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-xLstrikingly revealed that the activity of Bcl-xLto retrotranslocate activated Bax from membranes back into the cytosol is essential to reproduce or correctly predict experimental outcomes. These included the potency of Bcl-xLin 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-xLis necessary to strictly separate conditions of MOMP competency and resistance. Our results therefore identify Bax retrotranslocation by Bcl-xLas an indispensable component of the molecular switch by which Bcl-2 family members govern cellular death decisions.
@article{Hantusch2018,
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-xLstrikingly revealed that the activity of Bcl-xLto retrotranslocate activated Bax from membranes back into the cytosol is essential to reproduce or correctly predict experimental outcomes. These included the potency of Bcl-xLin 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-xLis necessary to strictly separate conditions of MOMP competency and resistance. Our results therefore identify Bax retrotranslocation by Bcl-xLas an indispensable component of the molecular switch by which Bcl-2 family members govern cellular death decisions.},
added-at = {2023-06-29T13:07:55.000+0200},
author = {Hantusch, Annika and Das, Kushal K and Garc{\'{i}}a-S{\'{a}}ez, Ana J and Brunner, Thomas and Rehm, Markus},
biburl = {https://puma.ub.uni-stuttgart.de/bibtex/25a5e3dca5d75e6e195f995bd071d2c94/fabian},
doi = {10.1038/s41419-018-0464-6},
interhash = {f97685aaa61d21d059746f91b6e91554},
intrahash = {5a5e3dca5d75e6e195f995bd071d2c94},
issn = {2041-4889},
journal = {Cell death {\&} disease},
keywords = {2018 izi morrison},
month = mar,
number = 4,
pages = 430,
pmid = {29567940},
timestamp = {2023-06-29T13:07:55.000+0200},
title = {{Bax retrotranslocation potentiates Bcl-xL's antiapoptotic activity and is essential for switch-like transitions between MOMP competency and resistance.}},
url = {http://www.ncbi.nlm.nih.gov/pubmed/29567940},
volume = 9,
year = 2018
}