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Nedd4L suppression in lung fibroblasts facilitates pathogenesis of lung fibrosis

  • Author Footnotes
    † Equal contribution to the work.
    Shuang Li
    Footnotes
    † Equal contribution to the work.
    Affiliations
    Department of Medicine, The University of Pittsburgh, Pittsburgh, PA
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  • Author Footnotes
    † Equal contribution to the work.
    Qinmao Ye
    Footnotes
    † Equal contribution to the work.
    Affiliations
    Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH

    Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH
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  • Jianxin Wei
    Affiliations
    Department of Medicine, The University of Pittsburgh, Pittsburgh, PA
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  • Sarah J Taleb
    Affiliations
    Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH

    Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH
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  • Heather Wang
    Affiliations
    Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH

    Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH
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  • Yingze Zhang
    Affiliations
    Department of Medicine, The University of Pittsburgh, Pittsburgh, PA
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  • Daniel J Kass
    Affiliations
    Department of Medicine, The University of Pittsburgh, Pittsburgh, PA
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  • Jeffrey C Horowitz
    Affiliations
    Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH

    The Department of Internal Medicine, The Ohio State University, Columbus, OH
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  • Jing Zhao
    Affiliations
    Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH

    Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH

    The Department of Internal Medicine, The Ohio State University, Columbus, OH
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  • Yutong Zhao
    Correspondence
    Reprint requests: Yutong Zhao, Department of Physiology and Cell Biology, The Ohio State University, 333 10th Avenue, Graves Hall 2166E, Columbus, OH, United States, 43210
    Affiliations
    Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH

    Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, OH

    The Department of Internal Medicine, The Ohio State University, Columbus, OH
    Search for articles by this author
  • Author Footnotes
    † Equal contribution to the work.
Published:October 15, 2022DOI:https://doi.org/10.1016/j.trsl.2022.10.002

      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)
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