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NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis

Endoplasmic reticulum (ER)–induced apoptosis and oxidative stress contribute to several chronic disease processes, yet molecular and cellular mechanisms linking ER stress and oxidative stress in the setting of apoptosis are poorly understood and infrequently explored in vivo. In this paper, we focus...

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Detalles Bibliográficos
Autores principales: Li, Gang, Scull, Christopher, Ozcan, Lale, Tabas, Ira
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002036/
https://www.ncbi.nlm.nih.gov/pubmed/21135141
http://dx.doi.org/10.1083/jcb.201006121
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author Li, Gang
Scull, Christopher
Ozcan, Lale
Tabas, Ira
author_facet Li, Gang
Scull, Christopher
Ozcan, Lale
Tabas, Ira
author_sort Li, Gang
collection PubMed
description Endoplasmic reticulum (ER)–induced apoptosis and oxidative stress contribute to several chronic disease processes, yet molecular and cellular mechanisms linking ER stress and oxidative stress in the setting of apoptosis are poorly understood and infrequently explored in vivo. In this paper, we focus on a previously elucidated ER stress–apoptosis pathway whose molecular components have been identified and documented to cause apoptosis in vivo. We now show that nicotinamide adenine dinucleotide phosphate reduced oxidase (NOX) and NOX-mediated oxidative stress are induced by this pathway and that apoptosis is blocked by both genetic deletion of the NOX subunit NOX2 and by the antioxidant N-acetylcysteine. Unexpectedly, NOX and oxidative stress further amplify CCAAT/enhancer binding protein homologous protein (CHOP) induction through activation of the double-stranded RNA–dependent protein kinase (PKR). In vivo, NOX2 deficiency protects ER-stressed mice from renal cell CHOP induction and apoptosis and prevents renal dysfunction. These data provide new insight into how ER stress, oxidative stress, and PKR activation can be integrated to induce apoptosis in a pathophysiologically relevant manner.
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spelling pubmed-30020362011-06-13 NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis Li, Gang Scull, Christopher Ozcan, Lale Tabas, Ira J Cell Biol Research Articles Endoplasmic reticulum (ER)–induced apoptosis and oxidative stress contribute to several chronic disease processes, yet molecular and cellular mechanisms linking ER stress and oxidative stress in the setting of apoptosis are poorly understood and infrequently explored in vivo. In this paper, we focus on a previously elucidated ER stress–apoptosis pathway whose molecular components have been identified and documented to cause apoptosis in vivo. We now show that nicotinamide adenine dinucleotide phosphate reduced oxidase (NOX) and NOX-mediated oxidative stress are induced by this pathway and that apoptosis is blocked by both genetic deletion of the NOX subunit NOX2 and by the antioxidant N-acetylcysteine. Unexpectedly, NOX and oxidative stress further amplify CCAAT/enhancer binding protein homologous protein (CHOP) induction through activation of the double-stranded RNA–dependent protein kinase (PKR). In vivo, NOX2 deficiency protects ER-stressed mice from renal cell CHOP induction and apoptosis and prevents renal dysfunction. These data provide new insight into how ER stress, oxidative stress, and PKR activation can be integrated to induce apoptosis in a pathophysiologically relevant manner. The Rockefeller University Press 2010-12-13 /pmc/articles/PMC3002036/ /pubmed/21135141 http://dx.doi.org/10.1083/jcb.201006121 Text en © 2010 Li et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Li, Gang
Scull, Christopher
Ozcan, Lale
Tabas, Ira
NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis
title NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis
title_full NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis
title_fullStr NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis
title_full_unstemmed NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis
title_short NADPH oxidase links endoplasmic reticulum stress, oxidative stress, and PKR activation to induce apoptosis
title_sort nadph oxidase links endoplasmic reticulum stress, oxidative stress, and pkr activation to induce apoptosis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002036/
https://www.ncbi.nlm.nih.gov/pubmed/21135141
http://dx.doi.org/10.1083/jcb.201006121
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