2. Academic Validation
  3. Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization

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

  • Nat Commun. 2020 Aug 26;11(1):4254. doi: 10.1038/s41467-020-18047-x.
Tzu-Han Lee 1,  Chih-Fan Yeh 1 2,  Ying-Tung Lee 1,  Ying-Chun Shih 1,  Yen-Ting Chen 1,  Chen-Ting Hung 1,  Ming-Yi You 1,  Pei-Chen Wu 1,  Tzu-Pin Shentu 3,  Ru-Ting Huang 3,  Yu-Shan Lin 1,  Yueh-Feng Wu 4,  Sung-Jan Lin 4 5 6,  Frank-Leigh Lu 7,  Po-Nien Tsao 6 7,  Tzu-Hung Lin 8,  Shen-Chuan Lo 8,  Yi-Shuan Tseng 1,  Wan-Lin Wu 1,  Chiung-Nien Chen 9,  Chau-Chung Wu 2 10,  Shuei-Liong Lin 6 11 12,  Anne I Sperling 3,  Robert D Guzy 3,  Yun Fang 3,  Kai-Chien Yang 13 14 15 16
Affiliations

Affiliations

  • 1 Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan.
  • 2 Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan.
  • 3 Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, IL, USA.
  • 4 Department of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei, Taiwan.
  • 5 Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
  • 6 Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan.
  • 7 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.
  • 8 Material and Chemical Research Laboratories, Industrial Technology Research Institute, Zhudong, Taiwan.
  • 9 Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.
  • 10 Department and Graduate Institute of Medical Education & Bioethics, National Taiwan University College of Medicine, Taipei, Taiwan.
  • 11 Department and Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
  • 12 Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
  • 13 Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, Taiwan. kcyang@ntu.edu.tw.
  • 14 Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, National Taiwan University Hospital, Taipei, Taiwan. kcyang@ntu.edu.tw.
  • 15 Research Center for Developmental Biology & Regenerative Medicine, National Taiwan University, Taipei, Taiwan. kcyang@ntu.edu.tw.
  • 16 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. kcyang@ntu.edu.tw.
PMID: 32848143 DOI: 10.1038/s41467-020-18047-x
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.

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