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ID 53647
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Author
Ryosuke, Nakato
Yu, Ohkubo
Akari, Konishi
Mari, Shibata
Yuki, Kaneko
Takao, Iwawaki
Tomohiro, Nakamura
Stuart A., Lipton
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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Published Date
2015
Publication Title
Scientific Reports
Volume
volume5
Publisher
Nature Publishing Group
Start Page
14812
ISSN
2045-2322
Content Type
Journal Article
Official Url
http://dx.doi.org/10.1038/srep14812
language
英語
Copyright Holders
© 2015 Nature Publishing Group
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Refereed
True
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PubMed ID