期刊
SCIENTIFIC REPORTS
卷 5, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/srep14812
关键词
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资金
- Ministry of Education, Culture, Sports and Technology (MEXT) of Japan [15H04649, 15K14952]
- Takeda Science Foundation
- Uehara Memorial Foundation
- Smoking Research Foundation
- NIH [P01 HD29587, R01 NS086890, P30 NS076411]
- Brain & Behavior Research Foundation Distinguished Investigator Award
- Grants-in-Aid for Scientific Research [15K14952, 15H04649] Funding Source: KAKEN
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 IRE1 alpha and PERK. While S-nitrosylation of IRE1 alpha inhibited its ribonuclease activity, S-nitrosylation of PERK activated its kinase activity and downstream phosphorylation/inactivation or eIF2 alpha. Site-directed mutagenesis of IRE1 alpha(Cys931) prevented S-nitrosylation and inhibition of its ribonuclease activity, indicating that Cys931 is the predominant site of S-nitrosylation. Importantly, cells overexpressing mutant IRE1 alpha(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.
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