Preventing oxidative stress: a new role for XBP1

http://www.nature.com/cdd/journal/v16/n6/abs/cdd200914a.html

Edited by SH Kaufmann

Y Liu^1,2,3, M Adachi^1,2, S Zhao³, M Hareyama⁴, A C Koong⁵, Dan Luo⁶, T A Rando⁶, K Imai² and Y Shinomura²

E-mail: adachi@sapmed.ac.jp

Abstract

Antioxidant molecules reduce oxidative stress and protect cells from reactive oxygen species (ROS)-mediated cellular damage and probably the development of cancer. We have investigated the contribution of X-box-binding protein (XBP1), a major endoplasmic reticulum stress-linked transcriptional factor, to cellular resistance to oxidative stress. After exposure to hydrogen peroxide (H₂O₂) or a strong ROS inducer parthenolide, loss of mitochondrial membrane potential (MMP) and subsequent cell death occurred more extensively in XBP1-deficient cells than wild-type mouse embryonic fibroblast cells, whereas two other anticancer agents induced death similarly in both cells. In XBP1-deficient cells, H₂O₂ exposure induced more extensive ROS generation and prolonged p38 phosphorylation, and expression of several antioxidant molecules including catalase was lower. Knockdown of XBP1 decreased catalase expression, enhanced ROS generation and MMP loss after H₂O₂ exposure, but extrinsic catalase supply rescued them. Overexpression of XBP1 recovered catalase expression in XBP1-deficient cells and diminished ROS generation after H₂O₂ exposure. Mutation analysis of the catalase promoter region suggests a pivotal role of CCAAT boxes, NF-Y-binding sites, for the XBP1-mediated enhancing effect. Taken together, these results indicate a protective role of XBP1 against oxidative stress, and its positive regulation of catalase expression may at least in part account for this function.

Keywords:

XBP1, ROS, catalase, oxidative stress, ER stress

Abbreviations:

XBP1, X-box-binding protein; ROS, reactive oxygen species; MEF, mouse embryonic fibroblast; ER, endoplasmic reticulum; NF-Y, nuclear factor Y