دورية أكاديمية
USP7 Promotes TGF-β1 Signaling by De-Ubiquitinating Smad2/Smad3 in Pulmonary Fibrosis.
| العنوان: | USP7 Promotes TGF-β1 Signaling by De-Ubiquitinating Smad2/Smad3 in Pulmonary Fibrosis. |
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| المؤلفون: | Tang F; Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006 Nanchang, Jiangxi, China., Gong H; Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006 Nanchang, Jiangxi, China., Ke T; Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006 Nanchang, Jiangxi, China., Yang W; Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006 Nanchang, Jiangxi, China., Yang Y; Department of Anesthesiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330006 Nanchang, Jiangxi, China., Liu Z; Department of Anesthesiology and Operative Medicine, Medical Center of Anesthesiology and Pain, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, 330209 Nanchang, Jiangxi, China. |
| المصدر: | Discovery medicine [Discov Med] 2024 Aug; Vol. 36 (187), pp. 1616-1626. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Discovery medicine Country of Publication: United States NLM ID: 101250006 Publication Model: Print Cited Medium: Internet ISSN: 1944-7930 (Electronic) Linking ISSN: 15396509 NLM ISO Abbreviation: Discov Med Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Timonium, MD : Discovery medicine Original Publication: 2001- : Baltimore, Md. : [Solariz], |
| مواضيع طبية MeSH: | Transforming Growth Factor beta1*/metabolism , Smad3 Protein*/metabolism , Ubiquitin-Specific Peptidase 7*/metabolism , Ubiquitin-Specific Peptidase 7*/genetics , Signal Transduction*/drug effects , Smad2 Protein*/metabolism , Bleomycin*/toxicity, Animals ; Mice ; Humans ; Pulmonary Fibrosis/metabolism ; Pulmonary Fibrosis/pathology ; Pulmonary Fibrosis/chemically induced ; Ubiquitination ; Idiopathic Pulmonary Fibrosis/metabolism ; Idiopathic Pulmonary Fibrosis/pathology ; Idiopathic Pulmonary Fibrosis/chemically induced ; Idiopathic Pulmonary Fibrosis/genetics ; Male ; Mice, Inbred C57BL ; Cell Line ; Lung/pathology ; Lung/metabolism ; Disease Models, Animal |
| مستخلص: | Background: Idiopathic pulmonary fibrosis (IPF) is a long-term, progressive, and irreversible pulmonary interstitial disease. The activation of Smad family member 2 (Smad2) and Smad3 transcription factors by transforming growth factor β-1 (TGF-β1) is a critical event in the pathogenesis of IPF. However, there is still a lack of understanding regarding the molecular mechanisms governing Smad2 and Smad3 proteins. Ubiquitin-specific protease 7 (USP7) is a deubiquitinase that plays a vital role in regulating protein stability within cells. However, its regulation of the TGF-β signaling pathway and its significance in IPF remain undiscovered. This study aims to clarify the function of USP7 in the TGF-β signaling pathway, while simultaneously exploring the specific molecular mechanisms involved. Additionally, this study seeks to evaluate the therapeutic potential of targeted USP7 inhibitors in IPF, thereby providing novel insights for the diagnosis and management of IPF. Methods: We first detected the expression of USP7 in lung tissues of mice with Bleomycin (BLM)-induced pulmonary fibrosis and in Beas-2B cells treated with or without TGF-β1 through Western blot analysis. Subsequently, we explored the influence of USP7 on fibrotic processes and the TGF-β1 signaling pathway, utilizing in vitro and in vivo studies. Finally, we assessed the effectiveness of USP7-specific inhibitors in an IPF murine model. Results: In the present study, USP7 was found to de-ubiquitinate Smad2 and Smad3, consequently increasing their stability and promoting the TGF-β1-induced production of profibrotic proteins including α-smooth muscle actin (α-SMA) and fibronectin 1 (FN-1). Inhibition or knockdown of USP7 resulted in decreased levels of Smad2 and Smad3 proteins, leading to reduced expression of FN-1, Collagen Type I Alpha 1 Chain (Col1A1), and α-SMA induced by TGF-β1 in human pulmonary epithelial cells. These findings demonstrate that overexpression of USP7 reduces Smad2/3 ubiquitination, whereas inhibition or knockdown of USP7 enhances their ubiquitination. USP7 is abundantly expressed in IPF lungs. The expressions of USP7, Smad2, and Smad3 were upregulated in bleomycin-induced lung injury. The USP7 inhibitor P22077 reduced the expression of FN-1 and type I collagen as well as Smad2/3 and collagen deposition in lung tissue in a model of pulmonary fibrosis induced by bleomycin. Conclusions: This study demonstrates that USP7 promotes TGF-β1 signaling by stabilizing Smad2 and Smad3. The contribution of USP7 to the progression of IPF indicates it may be a viable treatment target. |
| فهرسة مساهمة: | Keywords: Smad2; Smad3; idiopathic pulmonary fibrosis (IPF); transforming growth factor β-1 (TGF-β1); ubiquitin-specific protease 7 (USP7) |
| المشرفين على المادة: | 0 (Transforming Growth Factor beta1) 0 (Smad3 Protein) EC 3.4.19.12 (Ubiquitin-Specific Peptidase 7) 0 (Smad2 Protein) 11056-06-7 (Bleomycin) EC 3.4.19.12 (USP7 protein, human) EC 3.4.19.12 (Usp7 protein, mouse) 0 (SMAD3 protein, human) 0 (Smad3 protein, mouse) 0 (Smad2 protein, mouse) 0 (SMAD2 protein, human) |
| تواريخ الأحداث: | Date Created: 20240827 Date Completed: 20240827 Latest Revision: 20240828 |
| رمز التحديث: | 20240830 |
| DOI: | 10.24976/Discov.Med.202436187.148 |
| PMID: | 39190377 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1944-7930 |
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| DOI: | 10.24976/Discov.Med.202436187.148 |