ArticleEMBO reports2022
E3 ubiquitin ligase NEDD4L negatively regulates inflammation by promoting ubiquitination of MEKK2.
Article in EMBO reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 22 citations in OpenAlex.
- Review
- Endothelial NEDD4L exacerbates acute lung injury by targeting A20 for ubiquitination degradation.Respiratory research · 2026Article
- NEDD4L knockdown enhances synovial fibroblast migration, invasion, and inflammatory factor secretion via Wnt/β-Catenin signaling activation.Clinical rheumatology · 2026Article
- Tissue-Resident Macrophage-Derived E3 Ligase SMURF2 Restricts Autoimmune Inflammation by Mediating the Degradation of p-TBK1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The role of HECT-type E3 ubiquitin ligases in inflammation.Frontiers in immunology · 2026Review
- Structural basis for MEKK2 dimerization and substrate recognition.Nature communications · 2025Article
- DTX1 Modulates Microglial M1 Polarization and Exacerbates Neuroinflammation in Traumatic Brain Injury Model Rats through NF-κB/IRF5.Molecular neurobiology · 2025Article
- S-nitrosylated NEDD4 exacerbates gouty arthritis by upregulating NOD1 to induce pyroptosis.Genes and immunity · 2025Article
- Therapeutic potential of targeting the NEDD4L-eEF1A1 axis in cancer therapy.Acta biochimica et biophysica Sinica · 2025Article
- NEDD4L inhibits epithelial-mesenchymal transition in gastric cancer by mediating BICC1 ubiquitination.The Kaohsiung journal of medical sciences · 2025Article
- Identification of ubiquitination-related key biomarkers and immune infiltration in Crohn's disease by bioinformatics analysis and machine learning.Scientific reports · 2025Article
- Silencing NEDD4L Effectively Inhibits the Malignant Behaviors of Hepatocellular Carcinoma.Journal of hepatocellular carcinoma · 2025Article
- NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitination.Cell death discovery · 2024Article
- NEDD4L Suppresses Proliferation and Promotes Apoptosis by Ubiquitinating RAC2 Expression and Acts as a Prognostic Biomarker in Clear Cell Renal Cell Carcinoma.International journal of molecular sciences · 2024Article
- Ubiquitination of angiotensin-converting enzyme 2 contributes to the development of pulmonary arterial hypertension mediated by neural precursor cell-expressed developmentally down-regulated gene 4-Like.Respiratory research · 2024Article
- Role of Nedd4L in Macrophage Pro-Inflammatory Polarization Induced by Influenza A Virus and Lipopolysaccharide Stimulation.Microorganisms · 2024Article
- Article
- Targeting the deubiquitinaseOncology reports · 2023Review
- NEDD4L in human tumors: regulatory mechanisms and dual effects on anti-tumor and pro-tumor.Frontiers in pharmacology · 2023Review
- E3 ubiquitin ligase NEDD4L negatively regulates inflammation by promoting ubiquitination of MEKK2.EMBO reports · 2022Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberrant activation of inflammation signaling triggered by tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), and interleukin-17 (IL-17) is associated with immunopathology. Here, we identify neural precursor cells expressed developmentally down-regulated gene 4-like (NEDD4L), a HECT type E3 ligase, as a common negative regulator of signaling induced by TNF-α, IL-1, and IL-17. NEDD4L modulates the degradation of mitogen-activated protein kinase kinase kinase 2 (MEKK2) via constitutively and directly binding to MEKK2 and promotes its poly-ubiquitination. In interleukin-17 receptor (IL-17R) signaling, Nedd4l knockdown or deficiency enhances IL-17-induced p38 and NF-κB activation and the production of proinflammatory cytokines and chemokines in a MEKK2-dependent manner. We further show that IL-17-induced MEKK2 Ser520 phosphorylation is required not only for downstream p38 and NF-κB activation but also for NEDD4L-mediated MEKK2 degradation and the subsequent shutdown of IL-17R signaling. Importantly, Nedd4l-deficient mice show increased susceptibility to IL-17-induced inflammation and aggravated symptoms of experimental autoimmune encephalomyelitis (EAE) in IL-17R signaling-dependent manner. These data suggest that NEDD4L acts as an inhibitor of IL-17R signaling, which ameliorates the pathogenesis of IL-17-mediated autoimmune diseases.
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