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Integration of the Unfolded Protein and Oxidative Stress Responses through SKN-1/Nrf
The Unfolded Protein Response (UPR) maintains homeostasis in the endoplasmic reticulum (ER) and defends against ER stress, an underlying factor in various human diseases. During the UPR, numerous genes are activated that sustain and protect the ER. These responses are known to involve the canonical...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772064/ https://www.ncbi.nlm.nih.gov/pubmed/24068940 http://dx.doi.org/10.1371/journal.pgen.1003701 |
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author | Glover-Cutter, Kira M. Lin, Stephanie Blackwell, T. Keith |
author_facet | Glover-Cutter, Kira M. Lin, Stephanie Blackwell, T. Keith |
author_sort | Glover-Cutter, Kira M. |
collection | PubMed |
description | The Unfolded Protein Response (UPR) maintains homeostasis in the endoplasmic reticulum (ER) and defends against ER stress, an underlying factor in various human diseases. During the UPR, numerous genes are activated that sustain and protect the ER. These responses are known to involve the canonical UPR transcription factors XBP1, ATF4, and ATF6. Here, we show in C. elegans that the conserved stress defense factor SKN-1/Nrf plays a central and essential role in the transcriptional UPR. While SKN-1/Nrf has a well-established function in protection against oxidative and xenobiotic stress, we find that it also mobilizes an overlapping but distinct response to ER stress. SKN-1/Nrf is regulated by the UPR, directly controls UPR signaling and transcription factor genes, binds to common downstream targets with XBP-1 and ATF-6, and is present at the ER. SKN-1/Nrf is also essential for resistance to ER stress, including reductive stress. Remarkably, SKN-1/Nrf-mediated responses to oxidative stress depend upon signaling from the ER. We conclude that SKN-1/Nrf plays a critical role in the UPR, but orchestrates a distinct oxidative stress response that is licensed by ER signaling. Regulatory integration through SKN-1/Nrf may coordinate ER and cytoplasmic homeostasis. |
format | Online Article Text |
id | pubmed-3772064 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-37720642013-09-25 Integration of the Unfolded Protein and Oxidative Stress Responses through SKN-1/Nrf Glover-Cutter, Kira M. Lin, Stephanie Blackwell, T. Keith PLoS Genet Research Article The Unfolded Protein Response (UPR) maintains homeostasis in the endoplasmic reticulum (ER) and defends against ER stress, an underlying factor in various human diseases. During the UPR, numerous genes are activated that sustain and protect the ER. These responses are known to involve the canonical UPR transcription factors XBP1, ATF4, and ATF6. Here, we show in C. elegans that the conserved stress defense factor SKN-1/Nrf plays a central and essential role in the transcriptional UPR. While SKN-1/Nrf has a well-established function in protection against oxidative and xenobiotic stress, we find that it also mobilizes an overlapping but distinct response to ER stress. SKN-1/Nrf is regulated by the UPR, directly controls UPR signaling and transcription factor genes, binds to common downstream targets with XBP-1 and ATF-6, and is present at the ER. SKN-1/Nrf is also essential for resistance to ER stress, including reductive stress. Remarkably, SKN-1/Nrf-mediated responses to oxidative stress depend upon signaling from the ER. We conclude that SKN-1/Nrf plays a critical role in the UPR, but orchestrates a distinct oxidative stress response that is licensed by ER signaling. Regulatory integration through SKN-1/Nrf may coordinate ER and cytoplasmic homeostasis. Public Library of Science 2013-09-12 /pmc/articles/PMC3772064/ /pubmed/24068940 http://dx.doi.org/10.1371/journal.pgen.1003701 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Glover-Cutter, Kira M. Lin, Stephanie Blackwell, T. Keith Integration of the Unfolded Protein and Oxidative Stress Responses through SKN-1/Nrf |
title | Integration of the Unfolded Protein and Oxidative Stress Responses through SKN-1/Nrf |
title_full | Integration of the Unfolded Protein and Oxidative Stress Responses through SKN-1/Nrf |
title_fullStr | Integration of the Unfolded Protein and Oxidative Stress Responses through SKN-1/Nrf |
title_full_unstemmed | Integration of the Unfolded Protein and Oxidative Stress Responses through SKN-1/Nrf |
title_short | Integration of the Unfolded Protein and Oxidative Stress Responses through SKN-1/Nrf |
title_sort | integration of the unfolded protein and oxidative stress responses through skn-1/nrf |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772064/ https://www.ncbi.nlm.nih.gov/pubmed/24068940 http://dx.doi.org/10.1371/journal.pgen.1003701 |
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