دورية أكاديمية
Defining the mechanism of galectin-3-mediated TGF-β1 activation and its role in lung fibrosis.
| العنوان: | Defining the mechanism of galectin-3-mediated TGF-β1 activation and its role in lung fibrosis. |
|---|---|
| المؤلفون: | Calver JF; School of Medicine, University of Nottingham, Nottingham, United Kingdom; Stevenage Bioscience Catalyst, Galecto Biotech AB, Stevenage, United Kingdom., Parmar NR; School of Medicine, University of Nottingham, Nottingham, United Kingdom; Roche Products Limited, Welwyn Garden City, Hertfordshire, United Kingdom., Harris G; Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, Oxfordshire, United Kingdom., Lithgo RM; Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, Oxfordshire, United Kingdom; School of Biosciences, University of Nottingham, Loughborough, Leicestershire, United Kingdom; Membrane Protein Laboratory, Diamond Light Source, Rutherford Appleton Laboratory, Didcot, Oxfordshire, United Kingdom; Diamond Light Source, Diamond House, Rutherford Appleton Laboratories, Didcot, Oxfordshire, United Kingdom., Stylianou P; Institute for Lung Health, NIHR Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom; Leicester Institute for Structural and Chemical Biology, Henry Wellcome Building, University of Leicester, Leicester, United Kingdom., Zetterberg FR; Galecto Biotech AB, Sahlgrenska Science Park, Gothenburg, Sweden., Gooptu B; Institute for Lung Health, NIHR Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom; Leicester Institute for Structural and Chemical Biology, Henry Wellcome Building, University of Leicester, Leicester, United Kingdom., Mackinnon AC; Galecto Biotech AB, Nine Edinburgh BioQuarter, Edinburgh, United Kingdom., Carr SB; Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, Oxfordshire, United Kingdom; Department of Chemistry, University of Oxford, Oxford, Oxfordshire, United Kingdom., Borthwick LA; Fibrofind Ltd, Newcastle upon Tyne, United Kingdom; Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom., Scott DJ; Research Complex at Harwell, Rutherford Appleton Laboratory, Didcot, Oxfordshire, United Kingdom; School of Biosciences, University of Nottingham, Loughborough, Leicestershire, United Kingdom., Stewart ID; National Heart and Lung Institute, Imperial College London, London, United Kingdom., Slack RJ; Stevenage Bioscience Catalyst, Galecto Biotech AB, Stevenage, United Kingdom., Jenkins RG; National Heart and Lung Institute, Imperial College London, London, United Kingdom., John AE; National Heart and Lung Institute, Imperial College London, London, United Kingdom. Electronic address: a.john@imperial.ac.uk. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2024 Jun; Vol. 300 (6), pp. 107300. Date of Electronic Publication: 2024 Apr 18. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Transforming Growth Factor beta1*/metabolism , Galectin 3*/metabolism , Galectin 3*/genetics , Fibroblasts*/metabolism , Fibroblasts*/pathology , Idiopathic Pulmonary Fibrosis*/metabolism , Idiopathic Pulmonary Fibrosis*/pathology, Humans ; Lung/metabolism ; Lung/pathology ; Signal Transduction ; Receptor, Transforming Growth Factor-beta Type II/metabolism ; Receptor, Transforming Growth Factor-beta Type II/genetics ; Receptors, Transforming Growth Factor beta/metabolism ; Protein Binding ; Protein Serine-Threonine Kinases/metabolism ; Galectins/metabolism ; Collagen Type I/metabolism ; Cells, Cultured ; Blood Proteins |
| مستخلص: | Integrin-mediated activation of the profibrotic mediator transforming growth factor-β1 (TGF-β1), plays a critical role in idiopathic pulmonary fibrosis (IPF) pathogenesis. Galectin-3 is believed to contribute to the pathological wound healing seen in IPF, although its mechanism of action is not precisely defined. We hypothesized that galectin-3 potentiates TGF-β1 activation and/or signaling in the lung to promote fibrogenesis. We show that galectin-3 induces TGF-β1 activation in human lung fibroblasts (HLFs) and specifically that extracellular galectin-3 promotes oleoyl-L-α-lysophosphatidic acid sodium salt-induced integrin-mediated TGF-β1 activation. Surface plasmon resonance analysis confirmed that galectin-3 binds to αv integrins, αvβ1, αvβ5, and αvβ6, and to the TGFβRII subunit in a glycosylation-dependent manner. This binding is heterogeneous and not a 1:1 binding stoichiometry. Binding interactions were blocked by small molecule inhibitors of galectin-3, which target the carbohydrate recognition domain. Galectin-3 binding to β1 integrin was validated in vitro by coimmunoprecipitation in HLFs. Proximity ligation assays indicated that galectin-3 and β1 integrin colocalize closely (≤40 nm) on the cell surface and that colocalization is increased by TGF-β1 treatment and blocked by galectin-3 inhibitors. In the absence of TGF-β1 stimulation, colocalization was detectable only in HLFs from IPF patients, suggesting the proteins are inherently more closely associated in the disease state. Galectin-3 inhibitor treatment of precision cut lung slices from IPF patients' reduced Col1a1, TIMP1, and hyaluronan secretion to a similar degree as TGF-β type I receptor inhibitor. These data suggest that galectin-3 promotes TGF-β1 signaling and may induce fibrogenesis by interacting directly with components of the TGF-β1 signaling cascade. Competing Interests: Conflict of interests R. G. J. is a trustee for Action for Pulmonary Fibrosis. A. E. J. is a founder and shareholder of Alevin Therapeutics. J. F. C., F. R. Z., A. C. M., and R. J. S. are Galecto employees with shares/options in the company. N. R. P. is a Roche employee. L. A. B. is a director and shareholder of FibroFind. G. H., R. M. L., P. S., S. B. C., D. J. S., and I. D. S. declare that they have no conflict of interests with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: fibroblast; galectin; integrin; pulmonary fibrosis; transforming growth factor beta (TGF-β) |
| المشرفين على المادة: | 0 (Transforming Growth Factor beta1) 0 (Galectin 3) 0 (TGFB1 protein, human) 0 (LGALS3 protein, human) EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type II) 0 (Receptors, Transforming Growth Factor beta) EC 2.7.11.30 (TGFBR2 protein, human) EC 2.7.11.1 (Protein Serine-Threonine Kinases) 0 (Galectins) 0 (Collagen Type I) 0 (Blood Proteins) |
| تواريخ الأحداث: | Date Created: 20240419 Date Completed: 20240702 Latest Revision: 20240724 |
| رمز التحديث: | 20240725 |
| مُعرف محوري في PubMed: | PMC11134550 |
| DOI: | 10.1016/j.jbc.2024.107300 |
| PMID: | 38641066 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1083-351X |
|---|---|
| DOI: | 10.1016/j.jbc.2024.107300 |