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We have previously reported that protein disulfide isomerase (PDI) is <jats:italic>S<\/jats:italic>-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 <jats:italic>S<\/jats:italic>-nitrosylation of additional ER pathways that affect the unfolded protein response (UPR) in cell-based models of Parkinson\u2019s disease (PD). We demonstrate that nitric oxide (NO) can <jats:italic>S<\/jats:italic>-nitrosylate the ER stress sensors IRE1\u03b1 and PERK. While <jats:italic>S<\/jats:italic>-nitrosylation of IRE1\u03b1 inhibited its ribonuclease activity, <jats:italic>S<\/jats:italic>-nitrosylation of PERK activated its kinase activity and downstream phosphorylation\/inactivation or eIF2\u03b1. Site-directed mutagenesis of IRE1\u03b1(Cys931) prevented <jats:italic>S<\/jats:italic>-nitrosylation and inhibition of its ribonuclease activity, indicating that Cys931 is the predominant site of <jats:italic>S<\/jats:italic>-nitrosylation. Importantly, cells overexpressing mutant IRE1\u03b1(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.<\/jats:p>","DOI":"10.1038\/srep14812","type":"journal-article","created":{"date-parts":[[2015,10,8]],"date-time":"2015-10-08T09:41:38Z","timestamp":1444297298000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Regulation of the unfolded protein response via S-nitrosylation of sensors of endoplasmic reticulum stress"],"prefix":"10.1038","volume":"5","author":[{"given":"Ryosuke","family":"Nakato","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Ohkubo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akari","family":"Konishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mari","family":"Shibata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kaneko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takao","family":"Iwawaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohiro","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stuart A.","family":"Lipton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Uehara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,10,8]]},"reference":[{"key":"BFsrep14812_CR1","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/355033a0","volume":"355","author":"MJ Gething","year":"1992","unstructured":"Gething, M. 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