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  4. Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization
 
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Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization

Journal
Nature communications
Journal Volume
11
Journal Issue
1
Pages
4254
Date Issued
2020-08-26
Author(s)
CHAU-CHUNG WU  
CHIH-FAN YEH  
Lee, Ying-Tung
Shih, Ying-Chun
Chen, Yen-Ting
Hung, Chen-Ting
You, Ming-Yi
Wu, Pei-Chen
Shentu, Tzu-Pin
Huang, Ru-Ting
Lin, Yu-Shan
Wu, Yueh-Feng
SUNG-JAN LIN  
FRANK LEIGH LU  
PO-NIEN TSAO  
Lin, Tzu-Hung
Lo, Shen-Chuan
Tseng, Yi-Shuan
Wu, Wan-Lin
CHIUNG-NIEN CHEN  
Wu, Chau-Chung
SHUEI-LIONG LIN  
Sperling, Anne I
Guzy, Robert D
Fang, Yun
KAI-CHIEN YANG  
DOI
10.1038/s41467-020-18047-x
URI
https://scholars.lib.ntu.edu.tw/handle/123456789/592630
URL
https://scholars.lib.ntu.edu.tw/handle/123456789/546982
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.
Subjects
MESENCHYMAL TRANSITION; INHIBITION; INDUCTION; PATHWAYS; FAMILY; TRIAL
SDGs

[SDGs]SDG3

Other Subjects
cell component; cell organelle; gene; gene expression; numerical model; protein; public health; Mus; bleomycin; PC-TRP protein, mouse; protein disulfide isomerase; thioredoxin; transforming growth factor beta1; TXNDC5 protein, human; animal; C57BL mouse; chemistry; disease model; endoplasmic reticulum stress; fibrosing alveolitis; gene deletion; genetics; human; knockout mouse; lung fibrosis; male; metabolism; mouse; pathology; protein folding; protein stability; signal transduction; upregulation; Animals; Bleomycin; Disease Models, Animal; Endoplasmic Reticulum Stress; Gene Deletion; Humans; Idiopathic Pulmonary Fibrosis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Disulfide-Isomerases; Protein Folding; Protein Stability; Pulmonary Fibrosis; Receptor, Transforming Growth Factor-beta Type I; Signal Transduction; Thioredoxins; Transforming Growth Factor beta1; Up-Regulation
Publisher
NATURE PUBLISHING GROUP
Type
journal article

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