BAX and SMAC regulate bistable properties of the apoptotic caspase system

Abstract The initiation of apoptosis is a core mechanism in cellular biology by which organisms control the removal of damaged or unnecessary cells. The irreversible activation of caspases is essential for apoptosis, and mathematical models have demonstrated that the process is tightly regulated by...

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Autores principales:	Stephanie McKenna, Lucía García-Gutiérrez, David Matallanas, Dirk Fey
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0aa6015556d4479ab8ffa900097c7e38
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spelling	oai:doaj.org-article:0aa6015556d4479ab8ffa900097c7e382021-12-02T13:30:17ZBAX and SMAC regulate bistable properties of the apoptotic caspase system10.1038/s41598-021-82215-22045-2322https://doaj.org/article/0aa6015556d4479ab8ffa900097c7e382021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82215-2https://doaj.org/toc/2045-2322Abstract The initiation of apoptosis is a core mechanism in cellular biology by which organisms control the removal of damaged or unnecessary cells. The irreversible activation of caspases is essential for apoptosis, and mathematical models have demonstrated that the process is tightly regulated by positive feedback and a bistable switch. BAX and SMAC are often dysregulated in diseases such as cancer or neurodegeneration and are two key regulators that interact with the caspase system generating the apoptotic switch. Here we present a mathematical model of how BAX and SMAC control the apoptotic switch. Formulated as a system of ordinary differential equations, the model summarises experimental and computational evidence from the literature and incorporates the biochemical mechanisms of how BAX and SMAC interact with the components of the caspase system. Using simulations and bifurcation analysis, we find that both BAX and SMAC regulate the time-delay and activation threshold of the apoptotic switch. Interestingly, the model predicted that BAX (not SMAC) controls the amplitude of the apoptotic switch. Cell culture experiments using siRNA mediated BAX and SMAC knockdowns validated this model prediction. We further validated the model using data of the NCI-60 cell line panel using BAX protein expression as a cell-line specific parameter and show that model simulations correlated with the cellular response to DNA damaging drugs and established a defined threshold for caspase activation that could distinguish between sensitive and resistant melanoma cells. In summary, we present an experimentally validated dynamic model that summarises our current knowledge of how BAX and SMAC regulate the bistable properties of irreversible caspase activation during apoptosis.Stephanie McKennaLucía García-GutiérrezDavid MatallanasDirk FeyNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Stephanie McKenna Lucía García-Gutiérrez David Matallanas Dirk Fey BAX and SMAC regulate bistable properties of the apoptotic caspase system
description	Abstract The initiation of apoptosis is a core mechanism in cellular biology by which organisms control the removal of damaged or unnecessary cells. The irreversible activation of caspases is essential for apoptosis, and mathematical models have demonstrated that the process is tightly regulated by positive feedback and a bistable switch. BAX and SMAC are often dysregulated in diseases such as cancer or neurodegeneration and are two key regulators that interact with the caspase system generating the apoptotic switch. Here we present a mathematical model of how BAX and SMAC control the apoptotic switch. Formulated as a system of ordinary differential equations, the model summarises experimental and computational evidence from the literature and incorporates the biochemical mechanisms of how BAX and SMAC interact with the components of the caspase system. Using simulations and bifurcation analysis, we find that both BAX and SMAC regulate the time-delay and activation threshold of the apoptotic switch. Interestingly, the model predicted that BAX (not SMAC) controls the amplitude of the apoptotic switch. Cell culture experiments using siRNA mediated BAX and SMAC knockdowns validated this model prediction. We further validated the model using data of the NCI-60 cell line panel using BAX protein expression as a cell-line specific parameter and show that model simulations correlated with the cellular response to DNA damaging drugs and established a defined threshold for caspase activation that could distinguish between sensitive and resistant melanoma cells. In summary, we present an experimentally validated dynamic model that summarises our current knowledge of how BAX and SMAC regulate the bistable properties of irreversible caspase activation during apoptosis.
format	article
author	Stephanie McKenna Lucía García-Gutiérrez David Matallanas Dirk Fey
author_facet	Stephanie McKenna Lucía García-Gutiérrez David Matallanas Dirk Fey
author_sort	Stephanie McKenna
title	BAX and SMAC regulate bistable properties of the apoptotic caspase system
title_short	BAX and SMAC regulate bistable properties of the apoptotic caspase system
title_full	BAX and SMAC regulate bistable properties of the apoptotic caspase system
title_fullStr	BAX and SMAC regulate bistable properties of the apoptotic caspase system
title_full_unstemmed	BAX and SMAC regulate bistable properties of the apoptotic caspase system
title_sort	bax and smac regulate bistable properties of the apoptotic caspase system
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0aa6015556d4479ab8ffa900097c7e38
work_keys_str_mv	AT stephaniemckenna baxandsmacregulatebistablepropertiesoftheapoptoticcaspasesystem AT luciagarciagutierrez baxandsmacregulatebistablepropertiesoftheapoptoticcaspasesystem AT davidmatallanas baxandsmacregulatebistablepropertiesoftheapoptoticcaspasesystem AT dirkfey baxandsmacregulatebistablepropertiesoftheapoptoticcaspasesystem
_version_	1718392896307068928

BAX and SMAC regulate bistable properties of the apoptotic caspase system

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