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ID 53647
フルテキストURL
著者
Ryosuke, Nakato Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Yu, Ohkubo Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Akari, Konishi Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Mari, Shibata Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Yuki, Kaneko Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
Takao, Iwawaki Iwawaki laboratory, Education and Research Support Center, Graduate School of Medicine, Gunma University
Tomohiro, Nakamura Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute
Stuart A., Lipton Neuroscience and Aging Research Center, Sanford-Burnham-Prebys Medical Discovery Institute
Takashi, Uehara Department of Medicinal Pharmacology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University
抄録
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.
備考
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発行日
2015
出版物タイトル
Scientific Reports
5巻
出版者
Nature Publishing Group
開始ページ
14812
ISSN
2045-2322
資料タイプ
学術雑誌論文
オフィシャル URL
http://dx.doi.org/10.1038/srep14812
言語
English
著作権者
© 2015 Nature Publishing Group
論文のバージョン
publisher
査読
有り
DOI
PubMed ID