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

Tzu-Han Lee, Chih-Fan Yeh, Ying-Tung Lee, Ying-Chun Shih, Yen-Ting Chen, Chen-Ting Hung, Ming-Yi You, Pei-Chen Wu, Tzu-Pin Shentu, Ru-Ting Huang, Yu-Shan Lin, Yueh-Feng Wu, Sung-Jan Lin, Frank-Leigh Lu, Po-Nien Tsao, Tzu-Hung Lin, Shen-Chuan Lo, Yi-Shuan Tseng, Wan-Lin Wu, Chiung-Nien Chen, Chau-Chung Wu, Shuei-Liong Lin, Anne I. Sperling, Robert D. Guzy, Yun Fang and Kai-Chien Yang ()
Additional contact information
Tzu-Han Lee: National Taiwan University College of Medicine
Chih-Fan Yeh: National Taiwan University College of Medicine
Ying-Tung Lee: National Taiwan University College of Medicine
Ying-Chun Shih: National Taiwan University College of Medicine
Yen-Ting Chen: National Taiwan University College of Medicine
Chen-Ting Hung: National Taiwan University College of Medicine
Ming-Yi You: National Taiwan University College of Medicine
Pei-Chen Wu: National Taiwan University College of Medicine
Tzu-Pin Shentu: University of Chicago
Ru-Ting Huang: University of Chicago
Yu-Shan Lin: National Taiwan University College of Medicine
Yueh-Feng Wu: National Taiwan University
Sung-Jan Lin: National Taiwan University
Frank-Leigh Lu: National Taiwan University Hospital
Po-Nien Tsao: National Taiwan University
Tzu-Hung Lin: Industrial Technology Research Institute
Shen-Chuan Lo: Industrial Technology Research Institute
Yi-Shuan Tseng: National Taiwan University College of Medicine
Wan-Lin Wu: National Taiwan University College of Medicine
Chiung-Nien Chen: National Taiwan University Hospital
Chau-Chung Wu: National Taiwan University Hospital
Shuei-Liong Lin: National Taiwan University
Anne I. Sperling: University of Chicago
Robert D. Guzy: University of Chicago
Yun Fang: University of Chicago
Kai-Chien Yang: National Taiwan University College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18047-x

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