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Sci Rep ; 5: 14812, 2015 Oct 08.
Article in English | MEDLINE | ID: mdl-26446798

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.


Subject(s)
Endoplasmic Reticulum Stress/genetics , Endoribonucleases/metabolism , Nitric Oxide/metabolism , Protein Processing, Post-Translational , Protein Serine-Threonine Kinases/metabolism , Unfolded Protein Response/genetics , eIF-2 Kinase/metabolism , Amino Acid Substitution , Animals , Cell Death , Cell Line , Cell Line, Tumor , Cysteine/chemistry , Cysteine/metabolism , Endoplasmic Reticulum/metabolism , Endoribonucleases/genetics , Eukaryotic Initiation Factor-2/genetics , Eukaryotic Initiation Factor-2/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Mice , Models, Biological , Mutagenesis, Site-Directed , Neurons/cytology , Neurons/metabolism , Parkinson Disease/genetics , Parkinson Disease/metabolism , Parkinson Disease/pathology , Phosphorylation , Protein Serine-Threonine Kinases/genetics , Serine/chemistry , Serine/metabolism , Signal Transduction , eIF-2 Kinase/genetics
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