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

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.

SUBMITTER: Nakato R

PROVIDER: S-EPMC4597200 | biostudies-other | 2015 Oct

REPOSITORIES: biostudies-other

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DEV induce autophagy via the endoplasmic reticulum stress related unfolded protein response.

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2011-02-17 | E-GEOD-27349 | biostudies-arrayexpress

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Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR)

2011-02-17 | GSE27349 | GEO

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2021-03-04 | GSE153755 | GEO

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