Abstract
Endoplasmic reticulum (ER) stress is considered one of the pathological mechanisms of idiopathic pulmonary fibrosis (IPF). Therefore, we examined whether an ER stress regulator, Bax inhibitor-1 (BI-1), regulates collagen accumulation, which is both a marker of fibrosis and a pathological mechanism of fibrosis. The presence of BI-1 inhibited the transforming growth factor-β1-induced epithelial–mesenchymal transition of epithelial pulmonary cells and bleomycin-induced pulmonary fibrosis in a mouse model by enhancing collagen degradation, most likely by enhanced activation of the lysosomal V-ATPase through glycosylation. We also found a correlation between post-translational glycosylation of the V-ATPase and its associated chaperone, calnexin, in BI-1-overexpressing cells. BI-1-induced degradation of collagen through lysosomal V-ATPase glycosylation and the involvement of calnexin were confirmed in a bleomycin-induced fibrosis mouse model. These results highlight the regulatory role of BI-1 in IPF and reveal for the first time the role of lysosomal V-ATPase glycosylation in IPF.
Highlights
After an acute lung injury, lung epithelial cells regenerate and replace necrotic or apoptotic cells
A recent study proposed that endoplasmic reticulum (ER) stress is involved in Idiopathic pulmonary fibrosis (IPF) and that chemical regulation of ER stress may be a potential therapy for IPF.[19]
We examined the effect of the endogenous ER stress regulator, Bax inhibitor-1 (BI-1), on the transforming growth factor (TGF)-b1-induced epithelial–mesenchymal transition (EMT), in an in vitro model of IPF
Summary
After an acute lung injury, lung epithelial cells regenerate and replace necrotic or apoptotic cells. ER stress response is regulated by Bax inhibitor-1 (BI-1), an anti-apoptotic protein capable of inhibiting Bax activation and translocation to the mitochondria.[12] Physiologically, BI-1 is linked to the dynamic Ca2 þ environment of the ER.[13,14] Dynamic Ca2 þ status is linked to chaperones, such as calnexin and calreticulin.[15] Calnexin has an important role in glycoprotein folding as a lectin-like chaperone;[16] together with calreticulin, it performs quality control by retaining incompletely folded or misfolded proteins in the ER.[17,18] Our hypothesis was that the expression levels of BI-1-associated ER chaperones change according to the dynamic Ca2 þ status in BI-1-overexpressing cells (BI-1 cells), leading to an increase in the folding capacity of the ER. We examined BI-1-associated ER stress regulation and the intraER protein folding process in both in vitro and in vivo fibrosis models
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