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Nedd4L suppression in lung fibroblasts facilitates pathogenesis of lung fibrosis
Shuang Li1, Qinmao Ye2, Jianxin Wei1
1Department of Medicine, The University of Pittsburgh, Pittsburgh, PA.
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.
Insights
Nedd4L protein degradation is suppressed in lung fibrosis. Inhibiting E2F transcription factor restores Nedd4L, mitigating fibrosis and offering a potential therapeutic strategy for fibrotic disorders.
Area of Science:
- Cell Biology
- Molecular Biology
- Pulmonary Medicine
Background:
- Ubiquitination-mediated protein degradation is crucial in pulmonary fibrosis.
- Nedd4-like E3 ubiquitin ligase (Nedd4L) exhibits anti-inflammatory and anti-fibrotic properties.
- The regulation of Nedd4L in lung fibroblasts remains largely uncharacterized.
Purpose of the Study:
- To investigate the molecular regulation of Nedd4L expression in lung fibroblasts.
- To elucidate the role of Nedd4L in the pathogenesis of pulmonary fibrosis.
- To identify potential therapeutic targets for treating lung fibrosis.
Main Methods:
- Quantitative analysis of Nedd4L levels in patient samples and experimental models.
- Assessment of Nedd4L knockdown effects on TGF-β1 signaling and fibroblast differentiation.
- Investigation of Nedd4L's interaction with TGF-β receptor II (TβRII).
- Evaluation of E2F inhibition on Nedd4L expression and fibrosis progression.
Main Results:
- Nedd4L expression is significantly suppressed in lung myofibroblasts from IPF patients and in experimental fibrosis models.
- Nedd4L knockdown exacerbates TGF-β1-induced Smad2/3 phosphorylation and myofibroblast differentiation.
- Nedd4L directly targets TβRII for ubiquitination and degradation, a key step in TGF-β1 signaling.
- Inhibition of the transcriptional factor E2F restores Nedd4L levels and ameliorates experimental pulmonary fibrosis.
Conclusions:
- E2F-mediated suppression of Nedd4L contributes to the pathogenesis of lung fibrosis.
- Upregulating Nedd4L presents a promising therapeutic strategy for fibrotic diseases.
- Targeting the E2F-Nedd4L axis offers a novel approach for pulmonary fibrosis treatment.
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