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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.
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1 National Taiwan University College of Medicine, Department and Graduate Institute of Pharmacology, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241)
2 National Taiwan University College of Medicine, Department and Graduate Institute of Pharmacology, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241); National Taiwan University Hospital, Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, Taipei, Taiwan (GRID:grid.412094.a) (ISNI:0000 0004 0572 7815)
3 University of Chicago, Section of Pulmonary and Critical Care, Department of Medicine, Chicago, USA (GRID:grid.170205.1) (ISNI:0000 0004 1936 7822)
4 National Taiwan University, Department of Biomedical Engineering, College of Medicine and College of Engineering, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241)
5 National Taiwan University, Department of Biomedical Engineering, College of Medicine and College of Engineering, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241); National Taiwan University Hospital and College of Medicine, Department of Dermatology, Taipei, Taiwan (GRID:grid.412094.a) (ISNI:0000 0004 0572 7815); National Taiwan University, Research Center for Developmental Biology & Regenerative Medicine, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241)
6 National Taiwan University Hospital, Department of Pediatrics, Taipei, Taiwan (GRID:grid.412094.a) (ISNI:0000 0004 0572 7815)
7 National Taiwan University, Research Center for Developmental Biology & Regenerative Medicine, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241); National Taiwan University Hospital, Department of Pediatrics, Taipei, Taiwan (GRID:grid.412094.a) (ISNI:0000 0004 0572 7815)
8 Industrial Technology Research Institute, Material and Chemical Research Laboratories, Zhudong, Taiwan (GRID:grid.418030.e) (ISNI:0000 0001 0396 927X)
9 National Taiwan University Hospital, Department of Surgery, Taipei, Taiwan (GRID:grid.412094.a) (ISNI:0000 0004 0572 7815)
10 National Taiwan University Hospital, Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, Taipei, Taiwan (GRID:grid.412094.a) (ISNI:0000 0004 0572 7815); National Taiwan University College of Medicine, Department and Graduate Institute of Medical Education & Bioethics, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241)
11 National Taiwan University, Research Center for Developmental Biology & Regenerative Medicine, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241); National Taiwan University College of Medicine, Department and Graduate Institute of Physiology, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241); National Taiwan University Hospital, Division of Nephrology, Department of Internal Medicine, Taipei, Taiwan (GRID:grid.412094.a) (ISNI:0000 0004 0572 7815)
12 National Taiwan University College of Medicine, Department and Graduate Institute of Pharmacology, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241); National Taiwan University Hospital, Division of Cardiology, Department of Internal Medicine and Cardiovascular Center, Taipei, Taiwan (GRID:grid.412094.a) (ISNI:0000 0004 0572 7815); National Taiwan University, Research Center for Developmental Biology & Regenerative Medicine, Taipei, Taiwan (GRID:grid.19188.39) (ISNI:0000 0004 0546 0241); Academia Sinica, Institute of Biomedical Sciences, Taipei, Taiwan (GRID:grid.28665.3f) (ISNI:0000 0001 2287 1366)