論文

国際誌
2015年10月8日

Regulation of the unfolded protein response via S-nitrosylation of sensors of endoplasmic reticulum stress.

Scientific reports
  • Ryosuke Nakato
  • ,
  • Yu Ohkubo
  • ,
  • Akari Konishi
  • ,
  • Mari Shibata
  • ,
  • Yuki Kaneko
  • ,
  • Takao Iwawaki
  • ,
  • Tomohiro Nakamura
  • ,
  • Stuart A Lipton
  • ,
  • Takashi Uehara

5
開始ページ
14812
終了ページ
14812
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/srep14812

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.

リンク情報
DOI
https://doi.org/10.1038/srep14812
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/26446798
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597200
ID情報
  • DOI : 10.1038/srep14812
  • PubMed ID : 26446798
  • PubMed Central 記事ID : PMC4597200

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