title: Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing.
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.
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Femke
authors.initials: F
authors.lastname: Heindryckx
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: François
authors.initials: F
authors.lastname: Binet
authors.affiliation: Centre for Rheumatology and Connective Tissue Diseases, University College London, London, UK.
authors.forename: Markella
authors.initials: M
authors.lastname: Ponticos
authors.affiliation: Institute for Liver and Digestive Health, University College London, London, UK.
authors.forename: Krista
authors.initials: K
authors.lastname: Rombouts
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Joey
authors.initials: J
authors.lastname: Lau
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
authors.forename: Johan
authors.identifier: 0000-0002-2055-7776
authors.initials: J
authors.lastname: Kreuger
authors.affiliation: Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden Department of Radiology, Uppsala University Hospital, Uppsala, Sweden par.gerwins@mcb.uu.se.
authors.forename: Pär
authors.identifier: 0000-0003-3374-3372
authors.initials: P
authors.lastname: Gerwins
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism*; D005355:Fibrosis / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012867:Skin / Q000473:pathology; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1 / Q000378:metabolism*
chemical_list: D004722:Endoribonucleases; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; D000071717:X-Box Binding Protein 1; C533097:MIR150, human; C000605543:XBP1 protein, human; C528229:ERN1 protein, human
keywords: endoplasmic reticulum stress; fibrosis; liver cirrhosis; myofibroblast; scleroderma