ID | 53647 |
FullText URL | |
Author |
Ryosuke, Nakato
Yu, Ohkubo
Akari, Konishi
Mari, Shibata
Yuki, Kaneko
Takao, Iwawaki
Tomohiro, Nakamura
Stuart A., Lipton
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Abstract | Protein S-nitrosylation modulates important cellular processes, including neurotransmission, vasodilation, proliferation, and apoptosis in various cell types. We have previously reported that protein disulfide isomerase (PDI) is S-nitrosylated in brains of patients with sporadic neurodegenerative diseases. This modification inhibits PDI enzymatic activity and consequently leads to the accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) lumen. Here, we describe S-nitrosylation of additional ER pathways that affect the unfolded protein response (UPR) in cell-based models of Parkinson's disease (PD). We demonstrate that nitric oxide (NO) can S-nitrosylate the ER stress sensors IRE1α and PERK. While S-nitrosylation of IRE1α inhibited its ribonuclease activity, S-nitrosylation of PERK activated its kinase activity and downstream phosphorylation/inactivation or eIF2α. Site-directed mutagenesis of IRE1α(Cys931) prevented S-nitrosylation and inhibition of its ribonuclease activity, indicating that Cys931 is the predominant site of S-nitrosylation. Importantly, cells overexpressing mutant IRE1α(C931S) were resistant to NO-induced damage. Our findings show that nitrosative stress leads to dysfunctional ER stress signaling, thus contributing to neuronal cell death.
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Note | This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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Published Date | 2015
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Publication Title |
Scientific Reports
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Volume | volume5
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Publisher | Nature Publishing Group
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Start Page | 14812
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ISSN | 2045-2322
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Content Type |
Journal Article
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Official Url | http://dx.doi.org/10.1038/srep14812
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language |
English
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Copyright Holders | © 2015 Nature Publishing Group
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File Version | publisher
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Refereed |
True
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DOI | |
PubMed ID |