Inhibition of IRE1α-mediated XBP1 mRNA cleavage by XBP1 reveals a novel regulatory process during the unfolded protein response

Chalmers, F., van Lith, M., Sweeney, B., Cain, K. and Bulleid, N. J. (2017) Inhibition of IRE1α-mediated XBP1 mRNA cleavage by XBP1 reveals a novel regulatory process during the unfolded protein response. Wellcome Open Research, 2, 36. (doi: 10.12688/wellcomeopenres.11764.2) (PMID:29062910) (PMCID:PMC5645705)

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Background: The mammalian endoplasmic reticulum (ER) continuously adapts to the cellular secretory load by the activation of an unfolded protein response (UPR).  This stress response results in expansion of the ER, upregulation of proteins involved in protein folding and degradation, and attenuation of protein synthesis.  The response is orchestrated by three signalling pathways each activated by a specific signal transducer, either inositol requiring enzyme α (IRE1α), double-stranded RNA-activated protein kinase-like ER kinase (PERK) or activating transcription factor 6 (ATF6).  Activation of IRE1α results in its oligomerisation, autophosphorylation and stimulation of its ribonuclease activity.  The ribonuclease initiates the splicing of an intron from mRNA encoding the transcription factor, X-box binding protein 1 (XBP1), as well as degradation of specific mRNAs and microRNAs. Methods: To investigate the consequence of expression of exogenous XBP1, we generated a stable cell-line expressing spliced XBP1 mRNA under the control of an inducible promotor. Results: Following induction of expression, high levels of XBP1 protein were detected, which allowed upregulation of target genes in the absence of induction of the UPR.  Remarkably under stress conditions, the expression of exogenous XBP1 repressed splicing of endogenous XBP1 mRNA without repressing the activation of PERK. Conclusions: These results illustrate that a feedback mechanism exists to attenuate Ire1α ribonuclease activity in the presence of XBP1.

Item Type:Articles
Keywords:ER stress response, IRE1α, unfolded protein response, XBP1.
Glasgow Author(s) Enlighten ID:Van Lith, Dr Marcel and Bulleid, Professor Neil
Authors: Chalmers, F., van Lith, M., Sweeney, B., Cain, K., and Bulleid, N. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Wellcome Open Research
ISSN (Online):2398-502X
Copyright Holders:Copyright © 2017 Chalmers F et al.
First Published:First published in Wellcome Open Research 2:36
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
652801Protein Folding and Thiol Modification in the Mammalian Endoplasmic ReticulumNeil BulleidWellcome Trust (WELLCOTR)103720/Z/14/ZRI MOLECULAR CELL & SYSTEMS BIOLOGY
600711BRIC DOCTORATE PROGRAMME: Engineering cells for antibody productionNeil BulleidBiotechnology and Biological Sciences Research Council (BBSRC)BB/K004395/1RI MOLECULAR CELL & SYSTEMS BIOLOGY