Regulation of unfolded protein response by oxidative stress

2016 Fiscal Year Final Research Report

• Project/Area Number: 15K14952
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Okayama University
• Principal Investigator: Uehara Takashi 岡山大学, 医歯薬学総合研究科, 教授 (00261321)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 一酸化窒素 / 小胞体ストレス / 親電子性物質 / 酸化 / ニトロシル化 / 細胞死

Outline of Final Research Achievements

S-nitrosylation modulates important cellular processes in many cell types. We attempted to elucidate the effects of S-nitrosylation on unfolded protein response (UPR) pathway. We found that nitric oxide (NO) can S-nitrosylate the ER stress sensors IRE1α and PERK. However S-nitrosylation of IRE1α inhibited its ribonuclease activity, S-nitrosylation of PERK activated its kinase activity and downstream phosphorylation/inactivation or eIF2α. Overexpression of IRE1α(Cys931) prevented S-nitrosylation and inhibition of its enzymatic activity, indicating Cys931 is the predominant site of S-nitrosylation. These results indicated that nitrosative stress leads to dysfunctional ER stress signaling, thus contributing to neuronal cell death.

Free Research Field

薬理学