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Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. UCL, Ctr Rheumatol & Connect Tissue Dis, London, England.
UCL, Inst Liver & Digest Hlth, London, England.
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2016 (English)In: EMBO Molecular Medicine, ISSN 1757-4676, E-ISSN 1757-4684, Vol. 8, no 7, 729-744 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2016. Vol. 8, no 7, 729-744 p.
Keyword [en]
endoplasmic reticulum stress; fibrosis; liver cirrhosis; myofibroblast; scleroderma
National Category
Cell and Molecular Biology
Research subject
Molecular Medicine
Identifiers
URN: urn:nbn:se:uu:diva-300695DOI: 10.15252/emmm.201505925ISI: 000383632300005PubMedID: 27226027OAI: oai:DiVA.org:uu-300695DiVA: diva2:951991
Funder
Swedish Cancer SocietyWenner-Gren FoundationsSwedish Childhood Cancer Foundation
Note

De två första författarna delar förstaförfattarskapet.

De två sista författarna delar sistaförfattarskapet.

Available from: 2016-08-11 Created: 2016-08-11 Last updated: 2017-01-12Bibliographically approved

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Heindryckx, FemkeLau, JoeyKreuger, JohanGerwins, Pär
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