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ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response

The unfolded protein response (UPR) pathway senses unfolded proteins and regulates proteostasis and cell fate through activity of the transcription factors ATF4, ATF6, and XBP1 within a complex network of three main branches. Here, we investigated contributions of the three branches to UPR activity...

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Detalles Bibliográficos
Autores principales: Yang, Huan, Niemeijer, Marije, van de Water, Bob, Beltman, Joost B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005498/
https://www.ncbi.nlm.nih.gov/pubmed/32058971
http://dx.doi.org/10.1016/j.isci.2020.100860
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author Yang, Huan
Niemeijer, Marije
van de Water, Bob
Beltman, Joost B.
author_facet Yang, Huan
Niemeijer, Marije
van de Water, Bob
Beltman, Joost B.
author_sort Yang, Huan
collection PubMed
description The unfolded protein response (UPR) pathway senses unfolded proteins and regulates proteostasis and cell fate through activity of the transcription factors ATF4, ATF6, and XBP1 within a complex network of three main branches. Here, we investigated contributions of the three branches to UPR activity in single cells using microscopy-based quantification and dynamic modeling. BAC-GFP HepG2 reporter cell lines were exposed to tunicamycin, and activation of various UPR components was monitored for 24 h. We constructed a dynamic model to describe the adaptive UPR signaling network, for which incorporation of all three branches was required to match the data. Our calibrated model suggested that ATF6 shapes the early dynamics of pro-apoptotic CHOP. We confirmed this hypothesis by measurements beyond 24 h, by perturbing single siRNA knockdowns and by ATF6 measurements. Overall, our work indicates that ATF6 is an important regulator of CHOP, which in turn regulates cell fate decisions.
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spelling pubmed-70054982020-02-13 ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response Yang, Huan Niemeijer, Marije van de Water, Bob Beltman, Joost B. iScience Article The unfolded protein response (UPR) pathway senses unfolded proteins and regulates proteostasis and cell fate through activity of the transcription factors ATF4, ATF6, and XBP1 within a complex network of three main branches. Here, we investigated contributions of the three branches to UPR activity in single cells using microscopy-based quantification and dynamic modeling. BAC-GFP HepG2 reporter cell lines were exposed to tunicamycin, and activation of various UPR components was monitored for 24 h. We constructed a dynamic model to describe the adaptive UPR signaling network, for which incorporation of all three branches was required to match the data. Our calibrated model suggested that ATF6 shapes the early dynamics of pro-apoptotic CHOP. We confirmed this hypothesis by measurements beyond 24 h, by perturbing single siRNA knockdowns and by ATF6 measurements. Overall, our work indicates that ATF6 is an important regulator of CHOP, which in turn regulates cell fate decisions. Elsevier 2020-01-23 /pmc/articles/PMC7005498/ /pubmed/32058971 http://dx.doi.org/10.1016/j.isci.2020.100860 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Huan
Niemeijer, Marije
van de Water, Bob
Beltman, Joost B.
ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response
title ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response
title_full ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response
title_fullStr ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response
title_full_unstemmed ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response
title_short ATF6 Is a Critical Determinant of CHOP Dynamics during the Unfolded Protein Response
title_sort atf6 is a critical determinant of chop dynamics during the unfolded protein response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005498/
https://www.ncbi.nlm.nih.gov/pubmed/32058971
http://dx.doi.org/10.1016/j.isci.2020.100860
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