Open AccessEndoplasmic reticulum stress enhances fibrosis through IRE 1α‐mediated degradation of miR‐150 and XBP ‐1 splicing
Author(s) -
Heindryckx Femke,
Binet François,
Ponticos Markella,
Rombouts Krista,
Lau Joey,
Kreuger Johan,
Gerwins Pär
Publication year - 2016
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201505925
Subject(s) - endoplasmic reticulum , rna splicing , unfolded protein response , microbiology and biotechnology , chemistry , biology , biochemistry , gene , rna
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 IRE 1α signaling pathway, using the inhibitor 4μ8C, blocks TGF β‐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 IRE 1α −/− fibroblasts and expression of IRE 1α‐mutant proteins lacking endoribonuclease activity, we confirmed that IRE 1α plays an important role during myofibroblast activation. IRE 1α was shown to cleave miR‐150 and thereby to release the suppressive effect that miR‐150 exerted on α SMA expression through c‐Myb. Inhibition of IRE 1α 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.