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Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization
- Source :
- Nature Communications, Nature Communications, Vol 11, Iss 1, Pp 1-20 (2020)
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group UK, 2020.
-
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.<br />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.
- Subjects :
- 0301 basic medicine
Male
Protein Folding
Molecular biology
Pulmonary Fibrosis
Receptor, Transforming Growth Factor-beta Type I
General Physics and Astronomy
02 engineering and technology
Idiopathic pulmonary fibrosis
chemistry.chemical_compound
Mice
Thioredoxins
Pulmonary fibrosis
Protein disulfide-isomerase
lcsh:Science
Mice, Knockout
Multidisciplinary
Protein Stability
021001 nanoscience & nanotechnology
Endoplasmic Reticulum Stress
Up-Regulation
medicine.anatomical_structure
0210 nano-technology
Signal Transduction
Science
Protein Disulfide-Isomerases
Bleomycin
General Biochemistry, Genetics and Molecular Biology
Article
Transforming Growth Factor beta1
03 medical and health sciences
Downregulation and upregulation
medicine
Animals
Humans
Respiratory tract diseases
Lung
business.industry
Endoplasmic reticulum
General Chemistry
medicine.disease
Idiopathic Pulmonary Fibrosis
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
chemistry
Unfolded protein response
Cancer research
lcsh:Q
business
Gene Deletion
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....cc4672c919d4e7364bb4c044ef05faaa