Lee M-R, Lee G-H, Lee H-Y, Kim D-S, Chung M J, Lee Y C, Kim H-R, Chae H-J
Department of Pharmacology and Institute of Cardiovascular Research, Medical School, Chonbuk National University, Jeonju, Chonbuk, Republic of Korea.
Department of Pathology, Chonbuk National University Medical School, Jeonju, Chonbuk, Republic of Korea.
Cell Death Dis. 2014 Mar 13;5(3):e1113. doi: 10.1038/cddis.2014.86.
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.
内质网（ER）应激被认为是特发性肺纤维化（IPF）的病理机制之一。因此，我们研究了一种内质网应激调节因子，即Bax抑制因子-1（BI-1）是否调节胶原蛋白积累，胶原蛋白积累既是纤维化的标志物，也是纤维化的病理机制。在小鼠模型中，BI-1的存在通过增强胶原蛋白降解抑制了转化生长因子-β1诱导的肺上皮细胞上皮-间质转化和博莱霉素诱导的肺纤维化，最有可能是通过糖基化增强溶酶体V-ATP酶的激活来实现的。我们还发现，在BI-1过表达细胞中，V-ATP酶的翻译后糖基化与其相关伴侣钙连接蛋白之间存在相关性。在博莱霉素诱导的纤维化小鼠模型中证实了BI-1通过溶酶体V-ATP酶糖基化诱导胶原蛋白降解以及钙连接蛋白的参与。这些结果突出了BI-1在IPF中的调节作用，并首次揭示了溶酶体V-ATP酶糖基化在IPF中的作用。
