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

The Biochemical Journal
Stanley M H ChanT P Herbert

Abstract

Inositol-requiring enzyme 1 alpha (IRE1α) is an endoplasmic reticulum (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 diseases 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 (IC50 of 6.89 µM in cultured cells). However, in this paper, we demonstrate 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. In vitro we show that, 4µ8C effectively decreases xanthine/xanthine oxidase catalysed superoxide production with an IC50 of 0.2 µM whereas in cultured endothelial and clonal pancreatic β-cells, 4µ8C inhibits angiotensin II-induced ROS production with IC50 values 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 4µ8...Continue Reading

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Citations

Jul 20, 2019·Nature Chemical Biology·Claudio HetzJohn B Patterson
Aug 3, 2019·Proceedings of the National Academy of Sciences of the United States of America·Jonathan M HarnossAvi Ashkenazi
Sep 6, 2020·The Journal of Biological Chemistry·Julia M D Grandjean, R Luke Wiseman
Feb 11, 2021·Biomedicines·Natalia SiweckaIreneusz Majsterek
Feb 19, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Daniela Correia da SilvaDavid M Pereira
Aug 31, 2020·Trends in Cancer·Diana Pelizzari RaymundoEric Chevet
Jun 20, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Basel H AbuaitaMary X O'Riordan

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