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

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

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25 Citations (Scopus)

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.

Original languageEnglish
Article number14812
JournalScientific reports
Volume5
DOIs
Publication statusPublished - Oct 8 2015

ASJC Scopus subject areas

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    Nakato, R., Ohkubo, Y., Konishi, A., Shibata, M., Kaneko, Y., Iwawaki, T., Nakamura, T., Lipton, S. A., & Uehara, T. (2015). Regulation of the unfolded protein response via S-nitrosylation of sensors of endoplasmic reticulum stress. Scientific reports, 5, [14812]. https://doi.org/10.1038/srep14812