Nedd4L suppression in lung fibroblasts facilitates pathogenesis of lung fibrosis

Li, Shuang; Ye, Qinmao; Wei, Jianxin; Taleb, Sarah J; Wang, Heather; Zhang, Yingze; Kass, Daniel J.; Horowitz, Jeffrey C.; Zhao, Jing; Zhao, Yutong

doi:10.1016/j.trsl.2022.10.002

Cited by 8 publications

(8 citation statements)

References 31 publications

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“…We further explored the mechanism by which the circGRHPR/miR-665/NEDD4L axis regulates the progression of abnormal EMT in LECs. According to the results of previous studies, NEDD4L plays an anti-inflammatory and anti-fibrotic role in IPF by targeting ubiquitination and degradation of TGFBR2 (Li et al 2023 ). The signaling pathway of TGF-β1 plays a pivotal function in the advancement of IPF (Boutanquoi et al 2020 ).…”

Section: Discussionmentioning

confidence: 95%

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circGRHPR inhibits aberrant epithelial-mesenchymal transformation progression of lung epithelial cells associated with idiopathic pulmonary fibrosis

Wu,

Wang,

Zhang

et al. 2024

Cell Biol Toxicol

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Air pollution has greatly increased the risk of idiopathic pulmonary fibrosis (IPF). Circular RNAs (circRNAs) have been found to play a significant role in the advancement of IPF, but there is limited evidence of correlation between circRNAs and lung epithelial cells (LECs) in IPF. This research aimed to explore the influence of circRNAs on the regulation of EMT progression in LECs, with the objective of elucidating its mechanism and establishing its association with IPF. Our results suggested that the downregulation of circGRHPR in peripheral blood of clinical cases was associated with the diagnosis of IPF. Meanwhile, we found that circGRHPR was downregulated in transforming growth factor-beta1 (TGF-β1)–induced A549 and Beas-2b cells. It is a valid model to study the abnormal EMT progression of IPF-associated LECs in vitro. The overexpression of circGRHPR inhibited the abnormal EMT progression of TGF-β1-induced LECs. Furthermore, as the sponge of miR-665, circGRHPR released the expression of E3 ubiquitin-protein ligase NEDD4-like (NEDD4L), thus promoting its downstream transforming growth factor beta receptor 2 (TGFBR2) ubiquitination. It is helpful to reduce the response of LECs to TGF-β1 signaling. In summary, circGRHPR/miR-665/NEDD4L axis inhibited the abnormal EMT progression of TGF-β1-induced LECs by promoting TGFBR2 ubiquitination, which provides new ideas and potential targets for the treatment of IPF. Graphical Abstract Graphical headlights 1. Downregulation of circGRHPR in peripheral blood is associated with clinical diagnosis of IPF. 2. circGRHPR inhibits the abnormal EMT progression of TGF-β1-induced LECs in vitro. 3. circGRHPR/miR-665/NEDD4L axis inhibits the abnormal EMT progression of TGF-β1-induced LECs by promoting ubiquitination of TGFBR2 in vitro.

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Section: Discussionmentioning

confidence: 95%

“…NEDD4L alleviates experimental pulmonary fibrosis by targeting ubiquitination of TGFBR2 in lung fibroblasts (Li et al 2023 ). We found that circGRHPR affected the regulation of NEDD4L on TGFBR2 expression in LECs (Fig.…”

Section: Resultsmentioning

confidence: 99%

circGRHPR inhibits aberrant epithelial-mesenchymal transformation progression of lung epithelial cells associated with idiopathic pulmonary fibrosis

Wu,

Wang,

Zhang

et al. 2024

Cell Biol Toxicol

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“…In addition to TGF-β1, p-Smad2/3 can be regulated by several other factors; for example, Yu J.S. et al reported that p-Smad2/3 could be reduced through the inhibition of the PI3K/mTORC2 pathway [ 41 ]; SIRT1 was reported to interact with Smad2/3 to impede p-Smad2/3 nuclear translocation [ 42 ]; and NEDD4L, an E3 ubiquitin ligase, was shown to bind to p-Smad2/3 to degrade p-Smad2/3 [ 25 , 26 , 43 ]. On the basis of these studies, we determined that the stability of p-Smad2/3 was important for the transduction of TGF-β signaling and that ubiquitination was the essential factor for regulating protein stability.…”

Section: Discussionmentioning

confidence: 99%

The Upregulation of Leucine-Rich Repeat Containing 1 Expression Activates Hepatic Stellate Cells and Promotes Liver Fibrosis by Stabilizing Phosphorylated Smad2/3

Wang,

Li,

Guan

et al. 2024

IJMS

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Liver fibrosis poses a significant global health risk due to its association with hepatocellular carcinoma (HCC) and the lack of effective treatments. Thus, the need to discover additional novel therapeutic targets to attenuate liver diseases is urgent. Leucine-rich repeat containing 1 (LRRC1) reportedly promotes HCC development. Previously, we found that LRRC1 was significantly upregulated in rat fibrotic liver according to the transcriptome sequencing data. Herein, in the current work, we aimed to explore the role of LRRC1 in liver fibrosis and the underlying mechanisms involved. LRRC1 expression was positively correlated with liver fibrosis severity and significantly elevated in both human and murine fibrotic liver tissues. LRRC1 knockdown or overexpression inhibited or enhanced the proliferation, migration, and expression of fibrogenic genes in the human hepatic stellate cell line LX-2. More importantly, LRRC1 inhibition in vivo significantly alleviated CCl4-induced liver fibrosis by reducing collagen accumulation and hepatic stellate cells’ (HSCs) activation in mice. Mechanistically, LRRC1 promoted HSC activation and liver fibrogenesis by preventing the ubiquitin-mediated degradation of phosphorylated mothers against decapentaplegic homolog (Smad) 2/3 (p-Smad2/3), thereby activating the TGF-β1/Smad pathway. Collectively, these results clarify a novel role for LRRC1 as a regulator of liver fibrosis and indicate that LRRC1 is a promising target for antifibrotic therapies.

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“…Moreover, NEDD4L is also involved in Acquired Immune Deficiency Syndrome (AIDS) [23]. It directly catalyzes the K29-linked ubiquitination of tumor necrosis factor receptor-acting factor 3 (TRAF3), which regulates TRAF3 activity to promote innate immunity with antiviral effects [23] and plays a role in Wnt signaling, cellular autophagy, and pulmonary fibrosis [72][73][74].…”

Section: The Ubiquitin-proteasome System (Ups)mentioning

confidence: 99%

NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases

Xu,

Jiang,

et al. 2024

Biomolecules

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Protein ubiquitination is an enzymatic cascade reaction and serves as an important protein post-translational modification (PTM) that is involved in the vast majority of cellular life activities. The key enzyme in the ubiquitination process is E3 ubiquitin ligase (E3), which catalyzes the binding of ubiquitin (Ub) to the protein substrate and influences substrate specificity. In recent years, the relationship between the subfamily of neuron-expressed developmental downregulation 4 (NEDD4), which belongs to the E3 ligase system, and digestive diseases has drawn widespread attention. Numerous studies have shown that NEDD4 and NEDD4L of the NEDD4 family can regulate the digestive function, as well as a series of related physiological and pathological processes, by controlling the subsequent degradation of proteins such as PTEN, c-Myc, and P21, along with substrate ubiquitination. In this article, we reviewed the appropriate functions of NEDD4 and NEDD4L in digestive diseases including cell proliferation, invasion, metastasis, chemotherapeutic drug resistance, and multiple signaling pathways, based on the currently available research evidence for the purpose of providing new ideas for the prevention and treatment of digestive diseases.

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Nedd4L suppression in lung fibroblasts facilitates pathogenesis of lung fibrosis

Cited by 8 publications

References 31 publications

circGRHPR inhibits aberrant epithelial-mesenchymal transformation progression of lung epithelial cells associated with idiopathic pulmonary fibrosis

circGRHPR inhibits aberrant epithelial-mesenchymal transformation progression of lung epithelial cells associated with idiopathic pulmonary fibrosis

The Upregulation of Leucine-Rich Repeat Containing 1 Expression Activates Hepatic Stellate Cells and Promotes Liver Fibrosis by Stabilizing Phosphorylated Smad2/3

NEDD4 and NEDD4L: Ubiquitin Ligases Closely Related to Digestive Diseases

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