Chan, S. M.H., Lowe, M. P., Bernard, A., Miller, A. A. and Herbert, T. P. (2018) The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant. Biochemical Journal, 475(5), pp. 923-929. (doi: 10.1042/BCJ20170678) (PMID:29463644)
|
Text
158336.pdf - Accepted Version 400kB |
Abstract
Inositol Requiring Enzyme 1 alpha (IRE1α) is an ER-transmembrane endonuclease that is activated in response to ER stress as part of the unfolded protein response (UPR). Chronic activation of the UPR has been implicated in the pathogenesis of many common disease including diabetes, cancer and neurological pathologies such as Huntington's and Alzheimer's disease. 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde (4µ8C) is widely used as a specific inhibitor of IRE1α ribonuclease activity in mechanistic studies (IC50 of 6.89 µM in cultured cells). However, in this paper we showed that 4µ8C acts as a potent reactive oxygen species (ROS) scavenger both in a cell free assay and in cultured cells at concentrations lower than that widely used to inhibit IRE1α activity. We demonstrate that i 4µ8C effectively decreases xanthine/xanthine oxidase catalysed superoxide production with an IC50 of 0.2 µM. In cultured endothelial and clonal pancreatic beta-cells, 4µ8C inhibits angiotensin II-induced ROS production with IC50s of 1.92 and 0.29 µM respectively. In light of this discovery, conclusions reached using 4µ8C as an inhibitor of IRE1α should be carefully evaluated. However, this unexpected off-target effect of 4µ8C may prove therapeutically advantageous for the treatment of pathologies that are thought to be caused by, or exacerbated by, both oxidative and ER stress such as endothelial dysfunction and/or diabetes.
Item Type: | Articles |
---|---|
Additional Information: | This work was supported by a RMIT University research development fund awarded to T.P.H. |
Keywords: | ER stress, IRE1, oxidative stress, unfolded protein response |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Miller, Dr Alyson and Bernard, Mr Ashton |
Authors: | Chan, S. M.H., Lowe, M. P., Bernard, A., Miller, A. A., and Herbert, T. P. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | Biochemical Journal |
Publisher: | Portland Press Ltd. |
ISSN: | 0264-6021 |
ISSN (Online): | 1470-8728 |
Published Online: | 20 February 2018 |
Copyright Holders: | Copyright © 2018 The Authors |
First Published: | First published in Biochemical Journal 475(5):923-929 |
Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
University Staff: Request a correction | Enlighten Editors: Update this record