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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...

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Autores principales: Glover-Cutter, Kira M., Lin, Stephanie, Blackwell, T. Keith
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
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.
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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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