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
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Article info
Publication history
Published online: October 15, 2022
Accepted:
October 11,
2022
Received in revised form:
October 3,
2022
Received:
August 9,
2022
Identification
Copyright
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