BAX inhibitor-1-associated V-ATPase glycosylation enhances collagen degradation in pulmonary fibrosis

M-R Lee; G-H Lee; H-Y Lee; D-S Kim; M J Chung; Y C Lee; H-R Kim; H-J Chae

doi:10.1038/cddis.2014.86

BAX inhibitor-1-associated V-ATPase glycosylation enhances collagen degradation in pulmonary fibrosis

Cell Death Dis. 2014 Mar 13;5(3):e1113. doi: 10.1038/cddis.2014.86.

Authors

M-R Lee¹, G-H Lee¹, H-Y Lee¹, D-S Kim¹, M J Chung², Y C Lee³, H-R Kim⁴, H-J Chae¹

Affiliations

¹ Department of Pharmacology and Institute of Cardiovascular Research, Medical School, Chonbuk National University, Jeonju, Chonbuk, Republic of Korea.
² Department of Pathology, Chonbuk National University Medical School, Jeonju, Chonbuk, Republic of Korea.
³ Department of Internal Medicine, Chonbuk National University, Medical School, Jeonju, Chonbuk, Republic of Korea.
⁴ Department of Dental Pharmacology, School of Dentistry, Wonkwang University, Iksan, Chonbuk, Republic of Korea.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism*
Bleomycin
Calnexin / metabolism
Calreticulin / metabolism
Cell Line, Tumor
Collagen / metabolism*
Disease Models, Animal
Endoplasmic Reticulum Stress
Enzyme Activation
Epithelial Cells / enzymology*
Epithelial Cells / pathology
Epithelial-Mesenchymal Transition
Glycosylation
Humans
Lung / enzymology*
Lung / pathology
Lysosomes / metabolism
Male
Membrane Proteins / deficiency
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Mice, Knockout
Protein Processing, Post-Translational*
Proteolysis
Pulmonary Fibrosis / chemically induced
Pulmonary Fibrosis / enzymology*
Pulmonary Fibrosis / pathology
Time Factors
Transfection
Transforming Growth Factor beta1 / metabolism
Vacuolar Proton-Translocating ATPases / metabolism*

Substances

Apoptosis Regulatory Proteins
Calreticulin
Membrane Proteins
TGFB1 protein, human
TMBIM6 protein, human
Tmbim6 protein, mouse
Transforming Growth Factor beta1
Bleomycin
Calnexin
Collagen
Vacuolar Proton-Translocating ATPases