Abstract
Ubiquitination-mediated protein degradation is associated with the development of
pulmonary fibrosis. We and others have shown that Nedd4L plays anti-inflammatory and
anti-fibrotic roles by targeting lysophosphatidic acid receptor 1 (LPAR1), p-Smad2/3,
and β-catenin, and other molecules for their degradation in lung epithelial cells
and fibroblasts. However, the molecular regulation of Nedd4L expression in lung fibroblasts
has not been studied. In this study, we find that Nedd4L levels are significantly
suppressed in lung myofibroblasts in IPF patients and in experimental pulmonary fibrosis,
and in TGF-β1-treated lung fibroblasts. Nedd4L knockdown promotes TGF-β1-mediated
phosphorylation of Smad2/3 and lung myofibroblast differentiation. Mechanistically,
Nedd4L targets TGF-β receptor II (TβRII), the first key enzyme of TGF-β1-mediated
signaling, for its ubiquitination and degradation. Further, we show that inhibition
of transcriptional factor E2F rescues Nedd4L levels and mitigates experimental pulmonary
fibrosis. Together, our data reveal insight into mechanisms by which E2F-mediated
Nedd4L suppression contributes to the pathogenesis of lung fibrosis. This study provides
evidence showing that upregulation of Nedd4L is a potential therapeutic strategy to
treat fibrotic disorders including lung fibrosis.
Abbreviations:
IPF (idiopathic pulmonary fibrosis), TGF-β1 (transforming growth factor-β1), TβRII (TGF-β receptor II), ECM (extracellular matrix), FN (fibronectin), α-SMA (alpha-smooth muscle actin), BLM (bleomycin)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- The myofibroblast matrix: implications for tissue repair and fibrosis.The Journal of pathology. 2013; 229: 298-309
- The pathogenesis of idiopathic pulmonary fibrosis.Therapeutic advances in respiratory disease. 2010; 4: 367-388
- TGF-beta activation and lung fibrosis.Proceedings of the American Thoracic Society. 2012; 9: 130-136
- Novel mechanisms and treatment of idiopathic pulmonary fibrosis.Discovery medicine. 2015; 20: 145-153
- TGF-beta signal transduction and mesangial cell fibrogenesis.Am J Physiol Renal Physiol. 2003; 284: F243-F252
- Targeting TGF-beta Mediated SMAD Signaling for the Prevention of Fibrosis.Frontiers in pharmacology. 2017; 8: 461
- The impact of TGF-beta on lung fibrosis: from targeting to biomarkers.Proceedings of the American Thoracic Society. 2012; 9: 111-116
- Tgf-beta induced Erk phosphorylation of smad linker region regulates smad signaling.PloS one. 2012; 7: e42513
- Fibroblast-specific inhibition of TGF-beta1 signaling attenuates lung and tumor fibrosis.The Journal of clinical investigation. 2017; 127: 3675-3688
- E3 ubiquitin ligases as regulators of membrane protein trafficking and degradation.Traffic. 2005; 6: 429-441
- F-box protein FBXL19-mediated ubiquitination and degradation of the receptor for IL-33 limits pulmonary inflammation.Nature immunology. 2012; 13: 651-658
- Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling.Molecular cell. 2009; 36: 457-468
- NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor.The Biochemical journal. 2005; 386: 461-470
- Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury.EBioMedicine. 2016; 10: 195-203
- The Ubiquitin Ligase Nedd4L Regulates the Na/K/2Cl Co-transporter NKCC1/SLC12A2 in the Colon.The Journal of biological chemistry. 2017; 292: 3137-3145
- Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice.Nature communications. 2020; 11: 2012
- NEDD4L-induced beta-catenin ubiquitination suppresses the formation and progression of interstitial pulmonary fibrosis via inhibiting the CTHRC1/HIF-1alpha axis.Int J Biol Sci. 2021; 17: 3320-3330
- Inhibition of in vitro myogenic differentiation by cellular transcription factor E2F1.Cell Growth Differ. 1995; 6: 1299-1306
- E2F1 inhibition of transcription activation by myogenic basic helix-loop-helix regulators.J Cell Biochem. 1996; 62: 405-410
- Ablation of TRIP-Br2, a regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance.Nature medicine. 2013; 19: 217-226
- The CDK4-pRB-E2F1 pathway controls insulin secretion.Nature cell biology. 2009; 11: 1017-1023
- Acute loss of transcription factor E2F1 induces mitochondrial biogenesis in HeLa cells.J Cell Physiol. 2006; 209: 923-934
- E2F4/5 and p107 as Smad cofactors linking the TGFbeta receptor to c-myc repression.Cell. 2002; 110: 19-32
- TGF-beta induces growth suppression in multiple myeloma MM.1S cells via E2F1.Oncol Lett. 2017; 14: 1884-1888
- TGF-beta induces growth arrest in Burkitt lymphoma cells via transcriptional repression of E2F-1.The Journal of biological chemistry. 2009; 284: 1435-1442
- Gene Expression Changes Associated with Nintedanib Treatment in Idiopathic Pulmonary Fibrosis Fibroblasts: A Next-Generation Sequencing and Bioinformatics Study.J Clin Med. 2019; 8
- Overexpressing p130/E2F4 in mesenchymal stem cells facilitates the repair of injured alveolar epithelial cells in LPS-induced ARDS mice.Stem Cell Res Ther. 2019; 10: 74
- E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through the Egr-1/SHP/EID1 network.Hepatology. 2014; 60: 919-930
- Microarray analysis of differentially expressed genes in L929 mouse fibroblast cells exposed to leptin and hypoxia.Mol Med Rep. 2017; 16: 181-191
- De-ubiquitinating enzyme, USP11, promotes transforming growth factor beta-1 signaling through stabilization of transforming growth factor beta receptor II.Cell death & disease. 2016; 7: e2474
- The E2F1/USP11 positive feedback loop promotes hepatocellular carcinoma metastasis and inhibits autophagy by activating ERK/mTOR pathway.Cancer Lett. 2021; 514: 63-78
Article Info
Publication History
Published online: October 15, 2022
Accepted:
October 11,
2022
Received in revised form:
October 3,
2022
Received:
August 9,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
