%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 = {2018-03-28T08:52:58.000+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/cristiano}, 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 = {2019-01-17T12:21:32.000+0100}, 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 }