1. Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization
- Author
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Shuei-Liong Lin, Shen-Chuan Lo, Yu-Shan Lin, Y.-H. Lee, Frank-Leigh Lu, Kai-Chien Yang, Sung-Jan Lin, Tzu-Pin Shentu, Pei-Chen Wu, Chen-Ting Hung, Ying-Chun Shih, Robert D. Guzy, Chau-Chung Wu, Wan-Lin Wu, Yen-Ting Chen, Tzu-Han Lee, Anne I. Sperling, Ru-Ting Huang, Ming-Yi You, Yueh-Feng Wu, Chiung-Nien Chen, Yun Fang, Po-Nien Tsao, Chih-Fan Yeh, Yi-Shuan Tseng, and Tzu-Hung Lin
- Subjects
0301 basic medicine ,Male ,Protein Folding ,Molecular biology ,Pulmonary Fibrosis ,Receptor, Transforming Growth Factor-beta Type I ,General Physics and Astronomy ,02 engineering and technology ,Idiopathic pulmonary fibrosis ,chemistry.chemical_compound ,Mice ,Thioredoxins ,Pulmonary fibrosis ,Protein disulfide-isomerase ,lcsh:Science ,Mice, Knockout ,Multidisciplinary ,Protein Stability ,021001 nanoscience & nanotechnology ,Endoplasmic Reticulum Stress ,Up-Regulation ,medicine.anatomical_structure ,0210 nano-technology ,Signal Transduction ,Science ,Protein Disulfide-Isomerases ,Bleomycin ,General Biochemistry, Genetics and Molecular Biology ,Article ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Downregulation and upregulation ,medicine ,Animals ,Humans ,Respiratory tract diseases ,Lung ,business.industry ,Endoplasmic reticulum ,General Chemistry ,medicine.disease ,Idiopathic Pulmonary Fibrosis ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Unfolded protein response ,Cancer research ,lcsh:Q ,business ,Gene Deletion - Abstract
Pulmonary fibrosis (PF) is a major public health problem with limited therapeutic options. There is a clear need to identify novel mediators of PF to develop effective therapeutics. Here we show that an ER protein disulfide isomerase, thioredoxin domain containing 5 (TXNDC5), is highly upregulated in the lung tissues from both patients with idiopathic pulmonary fibrosis and a mouse model of bleomycin (BLM)-induced PF. Global deletion of Txndc5 markedly reduces the extent of PF and preserves lung function in mice following BLM treatment. Mechanistic investigations demonstrate that TXNDC5 promotes fibrogenesis by enhancing TGFβ1 signaling through direct binding with and stabilization of TGFBR1 in lung fibroblasts. Moreover, TGFβ1 stimulation is shown to upregulate TXNDC5 via ER stress/ATF6-dependent transcriptional control in lung fibroblasts. Inducing fibroblast-specific deletion of Txndc5 mitigates the progression of BLM-induced PF and lung function deterioration. Targeting TXNDC5, therefore, could be a novel therapeutic approach against PF., Pulmonary fibrosis is a major public health problem with unclear mechanism and limited therapeutic options. Here the authors show that a fibroblast-enriched endoplasmic reticulum protein, TXNDC5, promotes pulmonary fibrosis by stabilizing TGFBR1 and show the potential of TXNDC5 as a therapeutic target against pulmonary fibrosis.
- Published
- 2020