title: BAX inhibitor-1-associated V-ATPase glycosylation enhances collagen degradation in pulmonary fibrosis.
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.
authors.affiliation: Department of Pharmacology and Institute of Cardiovascular Research, Medical School, Chonbuk National University, Jeonju, Chonbuk, Republic of Korea.
authors.forename: M-R
authors.initials: MR
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Institute of Cardiovascular Research, Medical School, Chonbuk National University, Jeonju, Chonbuk, Republic of Korea.
authors.forename: G-H
authors.initials: GH
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Institute of Cardiovascular Research, Medical School, Chonbuk National University, Jeonju, Chonbuk, Republic of Korea.
authors.forename: H-Y
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and Institute of Cardiovascular Research, Medical School, Chonbuk National University, Jeonju, Chonbuk, Republic of Korea.
authors.forename: D-S
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Department of Pathology, Chonbuk National University Medical School, Jeonju, Chonbuk, Republic of Korea.
authors.forename: M J
authors.initials: MJ
authors.lastname: Chung
authors.affiliation: Department of Internal Medicine, Chonbuk National University, Medical School, Jeonju, Chonbuk, Republic of Korea.
authors.forename: Y C
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Dental Pharmacology, School of Dentistry, Wonkwang University, Iksan, Chonbuk, Republic of Korea.
authors.forename: H-R
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Institute of Cardiovascular Research, Medical School, Chonbuk National University, Jeonju, Chonbuk, Republic of Korea.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Chae
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001761:Bleomycin; D037281:Calnexin / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D006031:Glycosylation; D006801:Humans; D008168:Lung / Q000201:enzymology* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D037282:Calreticulin; D008565:Membrane Proteins; C508960:TGFB1 protein, human; C484209:TMBIM6 protein, human; C490015:Tmbim6 protein, mouse; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D037281:Calnexin; D003094:Collagen; D025262:Vacuolar Proton-Translocating ATPases