The inositol-requiring enzyme 1 (IRE1α) RNAse inhibitor, 4µ8C, is also a potent cellular antioxidant

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)

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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 > Institute of Cardiovascular and Medical Sciences
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

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