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

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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All data (except for supplementary figures 2c-g and 8c-8d) shown were obtained from at least 3 biological independent experiments. Supplementary figures 2c-g and 8c-8d were performed by 2 biological independent experiments.
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The animal work was approved by the institutional review boards of National Taiwan University and University of Chicago This study is composed of explanted lungs from 13 IPF patients obtained at the time of lung transplantation (2 female, 10 male and 1 sex not available) with average age (mean± SEM): 62±3.0 years old, fibrosis score 1/2/3 (<25% = 1, 25-75% = 2, >75% = 3): 0/2/11, and lungs unsuitable for transplantation from 9 non-IPF donor patients (3 female and 6 male) with average age (mean± SEM): 49±3.9 years old, fibrosis score 1/2/3 (<25% = 1, 25-75% = 2, >75% = 3): 8/1/0 Non-IPF control human lung samples were obtained from de-identified human lungs declined for transplantation (whose lungs were declined for transplantation, but whose next of kin had given consent for use in research) through the Regional Organ Bank of Illinois (ROBI) and Gift of Hope in collaboration with Dr. Julian Solway and Dr. Ann Sperling at the University of Chicago. IPF lung samples were obtained from de-identified explanted lungs of IPF patients undergoing lung transplantation at the University of Chicago. A written informed consent was obtained for each of the IPF patients. No self-selection bias.
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