XBP1U inhibits the XBP1S-mediated upregulation of the iNOS gene expression in mammalian ER stress response

Cellular Signalling
Fengjin GuoChuan-ju Liu

Abstract

Upregulation of the inducible nitric oxide synthase (iNOS) gene is associated with many pathological conditions such as endoplasmic reticulum (ER) stress, and X-box binding protein 1 (XBP1) is critical in mediating ER-stress responsive genes, including iNOS. Nonetheless, the mechanism by which XBP1 regulates iNOS during ER stress remains unexplored. Here we show that the active/spliced form of XBP1 protein, XBP1S, directly binds to the AABS (A-activator-binding site) in the iNOS promoter in vitro and in living cells. XBP1S exhibits dose-dependent activation of iNOS-specific reporter gene activity and endogenous iNOS expression. XBP1S is elevated whereas the unspliced form of XBP1, XBP1U, reduced in ER stress in HepG2 cells. In addition, XBP1U binds to XBP1S and this complex is associated with the iNOS promoter in response to ER stress. Furthermore, XBP1U acts as a negative mediator and suppresses XBP1S-mediated induction of iNOS. Collectively, we present the first evidence demonstrating the regulation of iNOS gene induction by the interaction between the spliced and unspliced forms of XBP1 in response to ER stress.

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Citations

Jun 7, 2012·Histochemistry and Cell Biology·Feng-Jin GuoChuanju Liu
Feb 20, 2014·Nature Immunology·Modesta N Njau, Joshy Jacob
Jun 18, 2014·Histochemistry and Cell Biology·Xiaofeng HanFeng-Jin Guo
Dec 9, 2014·Gut Microbes·Jennifer L GommermanJörg H Fritz
Feb 9, 2012·Molecular and Cellular Biochemistry·Xiangzhu LiFeng-Jin Guo
Oct 30, 2013·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Sven ReinhardtKristina Endres
Jan 7, 2020·American Journal of Physiology. Gastrointestinal and Liver Physiology·Atreju I LackeyJudith Storch
Jun 28, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Min JiangRan Zhang
Aug 7, 2012·The Journal of Biological Chemistry·Yanna LiuFeng-Jin Guo
Apr 27, 2019·Frontiers in Immunology·Laleh KhodadadiFalk Hiepe
Feb 13, 2021·Biomolecules·Kelly FéralChristian Touriol
Nov 14, 2017·Neuropharmacology·Luis E Santos, Sergio T Ferreira
Aug 7, 2021·Biomedicines·Sung-Min ParkJae-Seon So

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