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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...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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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. |
format | Online Article Text |
id | pubmed-7005498 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
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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