Endoplasmic reticulum stress enhances fibrosis through IRE1?-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 IRE1? signaling pathway, using the inhibitor 4?8C, blocks TGF?-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 IRE1?(-/-) fibroblasts and expression of IRE1?-mutant proteins lacking endoribonuclease activity, we confirmed that IRE1? plays an important role during myofibroblast activation. IRE1? was shown to cleave miR-150 and thereby to release the suppressive effect that miR-150 exerted on ?SMA expression through c-Myb. Inhibition of IRE1? 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.

SUBMITTER: Heindryckx F 

PROVIDER: S-EPMC4931288 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature