Heindryckx, F;
Binet, F;
Ponticos, M;
Rombouts, K;
Lau, J;
Kreuger, J;
Gerwins, P;
(2016)
Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing.
EMBO Molecular Medicine
, 8
(7)
pp. 729-744.
10.15252/emmm.201505925.
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Rombouts-K__Endoplasmic reticulum stress enhances fibrosis through IRE1a-mediated degradation of miR-150 and XBP-1 splicing..pdf Download (2MB) | Preview |
Abstract
ER stress results in activation of the unfolded protein response and has been implicated in the development of fibrotic diseases. In this study, we show that inhibition of the ER stress-induced IRE1α signaling pathway, using the inhibitor 4μ8C, blocks TGFβ-induced activation of myofibroblasts in vitro, reduces liver and skin fibrosis in vivo, and reverts the fibrotic phenotype of activated myofibroblasts isolated from patients with systemic sclerosis. By using IRE1α(-/-) fibroblasts and expression of IRE1α-mutant proteins lacking endoribonuclease activity, we confirmed that IRE1α plays an important role during myofibroblast activation. IRE1α was shown to cleave miR-150 and thereby to release the suppressive effect that miR-150 exerted on αSMA expression through c-Myb. Inhibition of IRE1α was also demonstrated to block ER expansion through an XBP-1-dependent pathway. Taken together, our results suggest that ER stress could be an important and conserved mechanism in the pathogenesis of fibrosis and that components of the ER stress pathway may be therapeutically relevant for treating patients with fibrotic diseases.
| Type: | Article |
|---|---|
| Title: | Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.15252/emmm.201505925 |
| Publisher version: | http://dx.doi.org/10.15252/emmm.201505925 |
| Language: | English |
| Additional information: | Copyright © The Authors, 2016. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Further details about CC BY licenses are available at http://creativecommons.org/licenses/by/4.0 |
| Keywords: | Endoplasmic reticulum stress, fibrosis, liver cirrhosis, myofibroblast, scleroderma |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1496326 |
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