Affinage

NEDD4L

E3 ubiquitin-protein ligase NEDD4-like · UniProt Q96PU5

Length
975 aa
Mass
111.9 kDa
Annotated
2026-04-29
100 papers in source corpus 43 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NEDD4L (Nedd4-2) is a HECT-domain E3 ubiquitin ligase that controls the surface abundance, trafficking, and turnover of a broad array of ion channels, transporters, receptors, and signaling proteins by catalyzing their ubiquitination through WW-domain recognition of PY motifs or adaptor-mediated substrate recruitment. Its best-characterized function is negative regulation of ENaC, NCC, and other renal ion transporters—loss of this regulation in mice causes salt-sensitive hypertension, progressive nephropathy, and neonatal lethality from premature lung fluid clearance, while in humans HECT-domain mutations cause periventricular nodular heterotopia through deregulated mTORC1/AKT signaling (PMID:12167587, PMID:23348737, PMID:21505443, PMID:27694961). NEDD4L activity is negatively regulated by SGK1-mediated phosphorylation (Ser-468) that recruits 14-3-3 proteins to sterically block WW-domain–substrate engagement, and positively regulated by c-Src phosphorylation at Y485 and by p38-MAPK signaling in response to elevated intracellular Na⁺/osmolarity, the latter forming a homeostatic negative-feedback loop for ENaC (PMID:16716084, PMID:30232011, PMID:35858421). Beyond epithelial transport, NEDD4L ubiquitinates TRAF3 (K29-linked) to promote type I interferon production, degrades SMAD2/3 to restrain TGF-β signaling and regulate autophagy, ubiquitinates Merlin to activate Hippo signaling, degrades GP130 (K27-linked) to suppress IL-6/STAT3 signaling, and targets MEKK2 for degradation as a negative feedback in IL-17 signaling (PMID:33608556, PMID:33106424, PMID:33058421, PMID:33769697, PMID:36161689).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2002 High

    Establishing NEDD4L as the physiological E3 ligase for ENaC resolved how PY-motif mutations in Liddle's syndrome cause channel hyperactivity: NEDD4L WW domains bind ENaC PY motifs, ubiquitinating the channel and reducing its surface density.

    Evidence Electrophysiology in Xenopus oocytes, co-immunoprecipitation, dominant-negative constructs across multiple labs

    PMID:11244092 PMID:12167587

    Open questions at the time
    • Ubiquitin chain type on ENaC not determined
    • E2 partner not yet identified at this stage
    • Regulation of NEDD4L activity itself unknown
  2. 2004 High

    Identification of UBE2E3 as the cognate E2 for the NEDD4L–ENaC axis revealed the minimal enzymatic machinery required for ENaC ubiquitination.

    Evidence Co-immunoprecipitation, catalytic-dead E2 mutant increases ENaC surface expression in oocytes and epithelial cells

    PMID:14993279

    Open questions at the time
    • Whether UBE2E3 is the exclusive E2 for all NEDD4L substrates not tested
    • No structural data on E2–HECT interaction
  3. 2005 High

    Discovery that SGK1 phosphorylates NEDD4L at Ser-468 to recruit 14-3-3 proteins explained how aldosterone signaling inhibits NEDD4L, thereby increasing ENaC surface expression—linking hormonal regulation to the E3 ligase.

    Evidence SPR, co-immunoprecipitation, electrophysiology in oocytes, phospho-site mutagenesis; isoform-domain mapping in MDCK/oocytes

    PMID:15677482 PMID:15814530 PMID:16716084

    Open questions at the time
    • Whether 14-3-3 binding affects NEDD4L activity toward non-ENaC substrates not tested
    • Structural basis of steric inhibition unresolved
  4. 2008 High

    An internal PY motif within the HECT domain was shown to engage NEDD4L's own WW domains, suppressing auto-ubiquitination; substrate engagement disrupts this autoinhibition, coupling ligase self-destruction to substrate processing.

    Evidence Pulse-chase, WW-domain binding assays, PY-motif mutagenesis, ubiquitination assays

    PMID:18498246

    Open questions at the time
    • Structural model of the intramolecular autoinhibited state lacking
    • Whether all substrates equally displace this intramolecular interaction unknown
  5. 2008 High

    NEDD4L was found to regulate cleaved/activated ENaC at two distinct endocytic steps and to stimulate HIV-1 budding through ESCRT ubiquitination, broadening NEDD4L function beyond steady-state channel regulation to membrane trafficking and viral egress.

    Evidence Biotinylation/electrophysiology with siRNA and DN constructs for ENaC; overexpression/depletion with viral titer assays for HIV budding

    PMID:18174164 PMID:18321968

    Open questions at the time
    • Whether NEDD4L is required for HIV budding under physiological expression levels unclear
    • Specific ubiquitin chain types on ESCRT substrates not determined
  6. 2009 High

    Demonstration that NEDD4L ubiquitinates surfactant protein-C at K6 via its PPDY motif and regulates CFTR trafficking expanded the substrate repertoire to lung surfactant processing and chloride channel quality control.

    Evidence GST pulldown, ubiquitination assay with K6/K34 mutagenesis in Sftpc−/− type II cells; Co-IP and siRNA knockdown for CFTR

    PMID:19423771 PMID:19617352

    Open questions at the time
    • Whether NEDD4L-mediated CFTR regulation is clinically targetable for cystic fibrosis not explored
    • In vivo validation for SP-C processing pending
  7. 2011 High

    Constitutive Nedd4-2 knockout mice died perinatally from premature lung fluid clearance due to ENaC overactivity, providing the first in vivo proof that NEDD4L is essential for ENaC regulation; hERG1 was identified as a cardiac substrate via PY-motif binding.

    Evidence KO mouse with lung phenotype, electrophysiology/Western blot; patch-clamp and ubiquitination assay for hERG1 in HEK293

    PMID:21463633 PMID:21505443

    Open questions at the time
    • Whether hERG1 regulation by NEDD4L is relevant in vivo not tested
    • Cardiac-specific KO phenotype not reported
  8. 2013 High

    Inducible nephron-specific Nedd4L deletion caused salt-sensitive hypertension rescued by thiazide, establishing NCC as a direct in vivo substrate alongside ENaC and demonstrating NEDD4L as a master regulator of renal sodium handling.

    Evidence Conditional KO mice, blood pressure telemetry, thiazide treatment, Western blot

    PMID:23348737

    Open questions at the time
    • Direct ubiquitination of NCC by NEDD4L not reconstituted in vitro at this point
    • Relative contribution of ENaC vs NCC to hypertension phenotype not fully dissected
  9. 2014 High

    A TrkA-P782S knock-in mouse demonstrated that NEDD4L–PY motif interaction controls TrkA trafficking and sensory neuron survival, extending NEDD4L function to neurotrophin receptor regulation and nociception.

    Evidence Knock-in mouse with altered TrkA trafficking, in vivo neuron counts, pain behavioral assays

    PMID:24760869

    Open questions at the time
    • Whether NEDD4L regulates other Trk receptors not determined
    • Ubiquitin chain type on TrkA not characterized
  10. 2016 High

    HECT-domain mutations in NEDD4L were identified as causal for periventricular nodular heterotopia, linking deregulated mTORC1/AKT signaling to a neurodevelopmental disorder; separately, NEDD4L was shown to ubiquitinate phospho-Syk in mast cells and SMAD2/3 in TGF-β signaling.

    Evidence Patient mutations with in utero electroporation and rapamycin rescue; mast cell-specific KO with anaphylaxis model; SMAD2/3 ubiquitination/degradation assays

    PMID:26130719 PMID:27694961 PMID:27786273

    Open questions at the time
    • Structural consequences of PNH mutations on HECT-domain catalysis unknown
    • Adaptor requirements for Syk recognition by NEDD4L (Ndfip1 dependence) not fully dissected
  11. 2017 High

    NEDD4L was shown to regulate NKCC1 abundance in the intestine (though indirectly) and to require NDFIP1/NDFIP2 adaptors for AQP2 ubiquitination, establishing adaptor-mediated substrate recruitment as a general mechanism for PY-motif-lacking substrates.

    Evidence Intestinal KO mice for NKCC1; membrane Y2H, Co-IP, ubiquitination assay with NDFIP PY-motif mutagenesis for AQP2

    PMID:28087701 PMID:28931009

    Open questions at the time
    • Whether NDFIP proteins mediate access to other substrates beyond AQP2 not systematically tested
    • Mechanism of indirect NKCC1 regulation unresolved
  12. 2018 High

    c-Src-mediated phosphorylation of NEDD4L at Y485 was identified as a positive activating modification, revealing a second regulatory phospho-switch opposing SGK1-mediated inhibition; Kir4.1/Kir5.1 heterotetramer was identified as a substrate via a phosphothreonine motif.

    Evidence Phosphoproteomics, Y485 mutagenesis, endothelial permeability assays; Co-IP, GST pulldown, patch-clamp, kidney-specific KO with TPVT motif mutagenesis

    PMID:29897283 PMID:30232011

    Open questions at the time
    • Whether Y485 phosphorylation is relevant in kidney epithelial cells not tested
    • Structural basis of phosphothreonine motif recognition by WW domains not determined
  13. 2020 High

    Multiple new substrates and regulatory circuits were established: Merlin ubiquitination (mono/di-Ub at K396) activates Hippo signaling; USP7-mediated deubiquitination stabilizes NEDD4L to degrade SMAD2 for autophagy-dependent protein clearance; Nedd4-2 KO kidneys develop progressive nephropathy rescued by amiloride; lung-specific KO causes pulmonary fibrosis.

    Evidence Co-IP/mutagenesis/Hippo reporters for Merlin; multi-organism genetic screen plus deubiquitination assay for USP7; constitutive/conditional KO mice with amiloride rescue for kidney; conditional lung KO with proteomics for fibrosis

    PMID:28862701 PMID:32332792 PMID:33058421 PMID:33106424

    Open questions at the time
    • Whether USP7–NEDD4L axis operates in renal/lung tissues not tested
    • Relative contribution of ENaC vs TGF-β pathway deregulation in lung fibrosis not dissected
  14. 2021 High

    NEDD4L was shown to promote innate antiviral immunity by catalyzing K29-linked ubiquitination of TRAF3 to enhance TBK1–IRF3 signaling and type I IFN production, revealing a non-degradative signaling ubiquitin chain function.

    Evidence Nedd4l-deficient mice and cells, ubiquitination assays with K29-specific analysis, mutagenesis of TRAF3 Cys56/Cys124, virus infection models

    PMID:33608556

    Open questions at the time
    • Whether K29-linked ubiquitin chains are a general feature of NEDD4L signaling substrates unknown
    • Structural basis for TRAF3 cysteine-targeted ubiquitination not resolved
  15. 2022 High

    A homeostatic feedback loop was revealed: Na+ influx through active ENaC raises intracellular [Na+]/osmolarity, activating p38-MAPK to stimulate NEDD4L catalytic activity (antagonized by WNKs), which then reduces ENaC surface density; separately, NEDD4L degrades MEKK2 via K29-linked ubiquitination as negative feedback in IL-17 signaling, and GP130 via K27-linked ubiquitination to suppress IL-6/STAT3.

    Evidence In vitro E3 assay with p38 modulators, electrophysiology, and WNK inhibitors for feedback loop; KO mice in EAE model, reciprocal Co-IP for MEKK2; KO mice in skin model with linkage-specific Ub mutants for GP130

    PMID:33769697 PMID:35858421 PMID:36161689

    Open questions at the time
    • Whether p38-MAPK directly phosphorylates NEDD4L or acts indirectly not resolved
    • Interplay between WNK inhibition and SGK1 phosphorylation of NEDD4L not integrated
  16. 2023 Medium

    NEDD4L substrate repertoire was further expanded to include GPX4 (K48-linked ubiquitination promoting ferroptosis), HIF-1α (14-3-3σ-assisted degradation), SGK1 itself (creating a mutual regulatory loop), and YBX1 (circNEIL3-mediated recruitment).

    Evidence Co-IP and ubiquitination assays for GPX4 in granulosa cells; phospho-site/Co-IP for HIF-1α; MS-validated interaction with half-life assays for SGK1; RNA pulldown and in vivo metastasis model for YBX1

    PMID:36662677 PMID:36961927 PMID:37345264 PMID:37494179

    Open questions at the time
    • Most substrates identified in single labs and await independent replication
    • Selectivity determinants for K48 vs K29 vs K27 chain linkage choice on different substrates remain undefined
    • Whether SGK1 degradation by NEDD4L operates in renal physiology not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: (1) the structural basis of NEDD4L autoinhibition and how different phospho-switches (S468, Y485, S448) coordinately tune activity; (2) how NEDD4L selects among K48, K29, and K27 ubiquitin chain linkages for different substrates; (3) whether newly identified substrates (GPX4, HIF-1α, YBX1, SGK1) represent physiologically relevant targets in vivo.
  • No full-length crystal/cryo-EM structure of NEDD4L
  • Ubiquitin chain-type selectivity mechanism unknown
  • Tissue-specific substrate hierarchies not systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 14 GO:0016874 ligase activity 5
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-392499 Metabolism of proteins 10 R-HSA-162582 Signal Transduction 6 R-HSA-382551 Transport of small molecules 5 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 1
Partners
NDFIP1NDFIP2SCNN1ASCNN1BSCNN1GSGK1TRAF3YWHAZ

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 NEDD4L (Nedd4-2) negatively regulates ENaC cell surface expression by binding to PY motifs (PPxY) in the C-termini of α, β, and γENaC subunits via its WW domains, leading to ubiquitination and reduced channel density at the plasma membrane; disruption of this interaction (as in Liddle's syndrome) causes elevated ENaC activity. Electrophysiology in Xenopus oocytes, co-immunoprecipitation, dominant-negative constructs, review of functional data American journal of physiology. Renal physiology High 11244092 12167587
2005 SGK1 phosphorylates NEDD4L at Ser-468 (between WW domains 2 and 3), which recruits 14-3-3 proteins to bind NEDD4L; this interaction maintains NEDD4L in an inactive phosphorylated state, thereby preventing ubiquitination and degradation of ENaC and increasing ENaC surface density. Co-immunoprecipitation, surface plasmon resonance, electrophysiology in Xenopus oocytes, phospho-site mutagenesis The Journal of biological chemistry High 15677482 16716084
2006 14-3-3 binding to SGK1-phosphorylated NEDD4L at Ser-468 sterically inhibits the interaction between NEDD4L WW domains and the PY motif of ENaC, thereby suppressing NEDD4L E3 ligase activity toward ENaC without affecting NEDD4L's own stability. Surface plasmon resonance, electrophysiology in Xenopus oocytes, phospho-site mutagenesis Biochemistry High 16716084
2004 The E2 ubiquitin-conjugating enzyme UBE2E3 physically interacts with NEDD4L and acts in concert with it to ubiquitinate ENaC; a catalytically inactive UBE2E3 mutant increases ENaC surface expression in a PY-motif-dependent manner. Co-immunoprecipitation, electrophysiology in Xenopus oocytes, catalytic mutant analysis, transepithelial Na+ transport assay Molecular and cellular biology High 14993279
2008 NEDD4L induces endocytosis of proteolytically cleaved/activated ENaC at the cell surface via a mechanism requiring the Nedd4-2 binding PY motifs on ENaC subunits, and also accelerates degradation of cleaved αENaC, reducing surface channel expression at two distinct steps in the endocytic pathway. Electrophysiology, biotinylation/surface expression assay, siRNA knockdown, dominant-negative overexpression in HEK293 and Fischer rat thyroid cells The Journal of biological chemistry High 18174164
2008 NEDD4L HECT domain contains an internal PY motif (LPXY) that is bound by its own WW domains, inhibiting auto-ubiquitination and stabilizing the ligase; substrate (ENaC) binding disrupts this intramolecular interaction, allowing NEDD4L self-ubiquitination and subsequent degradation after substrate ubiquitination. Pulse-chase experiments, WW domain binding assays, PY-motif mutagenesis, ubiquitination assays The Biochemical journal High 18498246
2011 Knockout of Nedd4-2 in mice leads to increased ENaC expression and activity in embryonic lung, causing premature fetal lung fluid clearance and perinatal lethality, demonstrating that NEDD4L is essential for correct regulation of ENaC expression in vivo. Constitutive knockout mouse, lung fluid clearance assay, electrophysiology, Western blot Nature communications High 21505443
2013 Inducible nephron-specific deletion of NEDD4L in adult mice causes salt-sensitive hypertension with upregulation of NCC (Na+Cl- cotransporter) and β/γENaC, demonstrating that NEDD4L directly regulates NCC in vivo and that its loss causes NCC-mediated hypertension. Tetracycline-inducible nephron-specific Nedd4L KO mice, metabolic cages, blood pressure telemetry, thiazide treatment, Western blot, protein quantification The Journal of clinical investigation High 23348737
2008 NEDD4L overexpression stimulates HIV-1 virus budding independent of canonical PTAP/YPXL late domains by ubiquitylating TSG101 and other ESCRT-I subunits, requiring NEDD4L's E3 ligase activity and TSG101. Overexpression/depletion in mammalian cells, infectious titer assays, siRNA knockdown, ubiquitylation assays, cytokinesis phenotype assay Journal of virology High 18321968
2016 Missense mutations in the NEDD4L HECT domain cause periventricular nodular heterotopia (PNH) by deregulating AKT and mTORC1 pathways; excess wild-type NEDD4L disrupts Dab1 and mTORC1 pathways, while PNH mutations specifically deregulate mTORC1 and AKT, affecting neurogenesis, neuronal positioning, and terminal translocation. In utero electroporation, rapamycin-based rescue, cellular expression data, patient mutations Nature genetics High 27694961
2021 NEDD4L positively regulates antiviral innate immunity by catalyzing K29-linked ubiquitination of TRAF3 at Cys56 and Cys124 (zinc-finger cysteines); this promotes TRAF3 interaction with TBK1, TBK1 phosphorylation, IRF3 phosphorylation, and subsequent type I interferon production. Nedd4l-deficient mice and cells, ubiquitination assays, Co-IP, mutagenesis of Cys56/Cys124, virus infection models Nature communications High 33608556
2020 Mass spectrometry identified LTF (lactotransferrin) as a direct NEDD4L-binding substrate; NEDD4L-mediated ubiquitination and degradation of LTF reduces intracellular iron accumulation, thereby limiting ferroptosis. Mass spectrometry, co-immunoprecipitation, siRNA knockdown, ferroptosis assay in cancer cells Biochemical and biophysical research communications Medium 32811647
2014 NEDD4L ubiquitinates TrkA via interaction with a PY motif (P782S mutation abolishes binding); defective TrkA ubiquitination in TrkAP782S knock-in mice leads to altered TrkA trafficking and degradation, increased survival of sensory neurons, and enhanced pain sensitivity. Knock-in mouse model, receptor trafficking assays, in vivo sensory neuron counts, pain behavioral assays The Journal of neuroscience High 24760869
2011 NEDD4L ubiquitylates the cardiac potassium channel hERG1 via a PY motif in hERG1's C-terminus; NEDD4L co-expression reduces whole-cell hERG1 currents and surface/total channel protein levels in HEK293 cells. Electrophysiology (patch-clamp), Western blot, biotinylation surface assay, co-immunoprecipitation, ubiquitylation assay, PY motif deletion Journal of molecular and cellular cardiology High 21463633
2017 NEDD4L regulates the Na+/K+/2Cl- co-transporter NKCC1 in the colon; conditional intestinal knockout of Nedd4L increases NKCC1 protein abundance and basolateral transporter activity, though NEDD4L does not directly co-immunoprecipitate with NKCC1, suggesting indirect regulation. Conditional intestinal KO mice (Nedd4L;Vil-Cre), short-circuit current measurements, Western blot, co-immunoprecipitation (negative result) The Journal of biological chemistry High 28087701
2018 NEDD4L binds to Kir5.1 via a phosphothreonine motif (TPVT, AA249-252) at its C-terminus; this interaction facilitates NEDD4L-mediated ubiquitination of the Kir4.1/Kir5.1 heterotetramer (but not Kir4.1 or Kir5.1 alone), reducing basolateral K+ conductance in the distal convoluted tubule. Co-immunoprecipitation, GST pull-down, ubiquitination assay, patch-clamp, Western blot, kidney-specific KO mice, site-directed mutagenesis of TPVT motif and catalytic inactive Nedd4-2C821A American journal of physiology. Renal physiology High 29897283
2017 NEDD4L mediates ubiquitination of glutamate transporters (GLT-1/GLAST) in astrocytes, inducing internalization and reducing membrane expression and glutamate uptake; Nedd4-2 knockdown restores glutamate transporter expression and function in a Parkinson's disease mouse model. Co-immunoprecipitation, siRNA knockdown, Western blot, glutamate uptake assay, MPTP mouse model Cell death & disease Medium 28151476
2009 NEDD4L directly binds the N-terminal propeptide of surfactant protein-C (SP-C) via the PPDY (PY) motif; Nedd4-2 WW domains capture the SP-C proprotein, and NEDD4L-mediated ubiquitination of SP-C at K6 is required for its lumenal relocation into multivesicular bodies, processing, and secretion. GST pulldown, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K6, K34, SPPDYS motif), adenovirus infection in Sftpc-/- type II cells American journal of respiratory cell and molecular biology High 19423771
2010 NEDD4L co-immunoprecipitates with occludin and ubiquitinates it via a PY motif in occludin's C-terminus; overexpression of NEDD4L reduces occludin at tight junctions and transiently increases paracellular conductance in collecting duct cells, while Nedd4-2 knockdown increases occludin levels and reduces paracellular conductance. Co-immunoprecipitation, ubiquitination assay, PY-motif mutagenesis, siRNA knockdown, Ca2+ switch assay, transepithelial resistance measurement American journal of physiology. Renal physiology High 20504882
2016 NEDD4L ubiquitinates phosphorylated Syk kinase in IgE-FcεRI-activated mast cells (facilitated by adaptor Ndfip1), suppressing downstream signaling; loss of Nedd4-2 or Ndfip1 in mast cells results in exacerbated IgE-mediated cutaneous anaphylaxis in vivo. Conditional mast cell-specific KO mice, anaphylaxis model, ubiquitination assay, signaling pathway analysis Nature communications High 27786273
2017 NDFIP1 and NDFIP2 serve as adaptors that bridge NEDD4L to AQP2 (aquaporin-2); NEDD4L cannot directly bind AQP2 but requires NDFIP proteins (via their PY motifs) to mediate AQP2 ubiquitination and degradation in renal collecting duct cells. Membrane yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, ubiquitination assay, PY-motif mutagenesis in NDFIP PloS one High 28931009
2018 GPCR protease-activated receptor-1 (PAR1) stimulates c-Src-mediated tyrosine phosphorylation of NEDD4L at Y485 (in the WW2-WW3 linker), activating its E3 ligase activity; NEDD4L Y485 phosphorylation is required for PAR1-stimulated p38 activation and endothelial barrier disruption. Mass spectrometry (phosphoproteomics), site-directed mutagenesis (Y485), electrophysiology/permeability assays, c-Src inhibitor treatment Cell reports High 30232011
2020 NEDD4L ubiquitinates Merlin (NF2 tumor suppressor) primarily at K396 (mono/di-ubiquitination), facilitated by scaffold protein AMOTL1; this ubiquitination is promoted by S518 dephosphorylation in response to Ca2+ signaling or cell detachment and is required for Merlin binding to Lats1 and Hippo pathway activation. Co-immunoprecipitation, ubiquitination assay, mutagenesis (K396R, S518), siRNA knockdown, Hippo pathway reporter assays, Ca2+ signaling experiments EMBO reports High 33058421
2020 USP7 deubiquitinates NEDD4L, stabilizing it; NEDD4L in turn ubiquitinates and degrades SMAD2, a transcription modulator of TGF-β/autophagy; inhibition of USP7 activates this NEDD4L-SMAD2 axis to enhance clearance of misfolded proteins. C. elegans and Drosophila genetic screens, deubiquitination assay, Western blot, autophagy assay, SMAD2 protein stability measurement in mammalian neurons Proceedings of the National Academy of Sciences of the United States of America High 33106424
2009 NEDD4L (Nedd4-2) binds to both wild-type and ΔF508-CFTR via co-immunoprecipitation; the SGK1/Nedd4-2 signaling pathway regulates CFTR ubiquitination and trafficking—SGK1 knockdown blocks dexamethasone-activated ΔF508-CFTR rescue and Nedd4-2 knockdown corrects ΔF508-CFTR trafficking. Co-immunoprecipitation, siRNA knockdown of Nedd4-2 and SGK1, CFTR half-life measurement, ubiquitination assay The Journal of biological chemistry Medium 19617352
2022 NEDD4L mediates K29-linked ubiquitination and proteasomal degradation of MEKK2 by constitutively and directly binding MEKK2; IL-17-induced Ser520 phosphorylation of MEKK2 is required both for downstream p38/NF-κB activation and for NEDD4L-mediated MEKK2 degradation, creating a negative feedback in IL-17R signaling. Co-immunoprecipitation, ubiquitination assay, Nedd4l KO mice (EAE model), siRNA knockdown, phospho-site mutagenesis EMBO reports High 36161689
2021 NEDD4L mediates ubiquitination and degradation of GP130 (IL-6 receptor subunit) via Lys-27-linked ubiquitination; NEDD4L directly interacts with GP130, suppressing IL-6/STAT3 signaling and keratinocyte hyperplasia. Co-immunoprecipitation, ubiquitination assay, Nedd4l KO (imiquimod skin model), Western blot, linkage-specific ubiquitin mutants EMBO reports High 33769697
2022 Elevated intracellular Na+ ([Na+]i) and hyperosmolarity stimulate NEDD4L catalytic activity via activation of p38-MAPK; this is inhibited by WNKs. Active ENaC (cleaved by Furin) increases [Na+]i and osmolarity, which feeds back to enhance NEDD4L E3 activity—a negative feedback loop without altering Nedd4-2:ENaC binding. In vitro E3 ubiquitination assay, p38 inhibitor/activator experiments, ENaC surface expression (biotinylation), electrophysiology, Furin inhibitor, amiloride treatment, WNK inhibition Proceedings of the National Academy of Sciences of the United States of America High 35858421
2016 Nedd4-2 is a direct transcriptional target of p53; elevated neuronal activity triggers Mdm2-dependent p53 degradation, which reduces Nedd4-2 expression, increasing neural network synchrony; reducing Nedd4-2 expression directly elevates synchrony and seizure susceptibility in mice. Primary cortical neuron cultures, pharmacological manipulation (Picrotoxin, Mdm2 inhibitor, p53 inhibitor), Nedd4-2 knockdown mice, kainic acid seizure model Molecular brain Medium 27000207
2019 PLPP/CIN (pyridoxal-5'-phosphate phosphatase/chronophin) dephosphorylates NEDD4L at Ser448, activating NEDD4L-mediated ubiquitination of the GluA1 AMPA receptor subunit; this reduces AMPAR-mediated currents and modulates neuronal excitability. PLPP/CIN deletion and overexpression in neurons, ubiquitination assay, electrophysiology (AMPAR currents), phospho-site analysis Cell death & disease Medium 31320629
2023 NEDD4L directly interacts with GPX4 and promotes its K48-linked ubiquitination and proteasomal degradation, facilitating ferroptosis in granulosa cells; NEDD4L overexpression reduces cell viability and elevates ferroptosis markers. Co-immunoprecipitation, ubiquitination assay, ferroptosis markers (MDA, ROS, iron, GSH), CCK-8, ferroptosis inhibitor rescue Endocrine connections Medium 36662677
2023 circNEIL3 directly interacts with oncogenic YBX1 protein, recruiting NEDD4L to mediate proteasomal degradation of YBX1; this suppresses tumor metastasis in colorectal cancer. Co-immunoprecipitation, RNA pulldown, ubiquitination assay, in vivo metastasis models Proceedings of the National Academy of Sciences of the United States of America Medium 36961927
2020 Nedd4-2 knockout mice show progressive kidney injury with elevated ENaC and NCC expression, increased Na+ reabsorption, and nephropathy; partial therapeutic amelioration by amiloride (ENaC blocker) confirms ENaC as the primary in vivo renal target of NEDD4L. Constitutive and nephron-specific KO mice, amiloride treatment, Western blot, histological analysis of fibrosis and injury Cell death and differentiation High 28862701
2020 Conditional deletion of NEDD4L in lung epithelial cells in adult mice produces progressive pulmonary fibrosis with features of IPF, associated with dysregulation of ENaC (affecting airway surface hydration/mucus clearance) and TGF-β signaling. Conditional lung epithelial KO mice, lung function testing, proteomics, pirfenidone treatment Nature communications High 32332792
2021 Non-SUMOylated CRMP2 forms a complex with Nedd4-2, Numb, and Eps15 to promote clathrin-mediated endocytosis of NaV1.7; silencing Nedd4-2 in DRG neurons from CRMP2-SUMO-null mice restores NaV1.7 sodium currents. CRMP2 knock-in mice, siRNA knockdown of complex members in DRG neurons, electrophysiology (sodium currents), clathrin assembly inhibition Molecular brain Medium 33478555
2022 NEDD4L physically binds the 19S proteasome subunit and limits its proteolytic activity; NEDD4L suppression reduces autophagy and bortezomib sensitivity in multiple myeloma cells. Co-immunoprecipitation, proteasome activity assay, autophagy assay, siRNA knockdown, in vivo xenograft Cell death & disease Medium 35236820
2013 NEDD4L inhibits canonical WNT signaling at or below the level of β-catenin in a manner requiring its catalytic (E3 ligase) activity, as catalytically inactive NEDD4L did not inhibit WNT signaling. Luciferase WNT reporter assay, catalytic mutant NEDD4L expression, Western blot in colorectal cancer cells PloS one Medium 24312311
2005 Different NEDD4L isoforms (full-length with C2 domain, ΔC2, and ΔWW2,3) differentially associate with and regulate ENaC; WW domains 2 and 3 are required for ENaC interaction and functional inhibition, while the C2 domain targets NEDD4L to the plasma membrane in response to elevated intracellular Ca2+. Co-immunoprecipitation, electrophysiology in Xenopus oocytes and collecting duct cells, subcellular localization in MDCK cells American journal of physiology. Renal physiology High 15814530
2023 NEDD4L mediates K48-linked poly-ubiquitin-dependent degradation of SGK1 (via the NEDD4L-Ubch5 complex); p16 protein interferes with this interaction by binding to the N-terminus of SGK1, blocking NEDD4L-mediated SGK1 degradation. Mass spectrometry, co-immunoprecipitation, GST pull-down, SGK1 half-life measurement, ubiquitination assay with K48-specific antibodies Clinical and translational medicine Medium 37345264
2020 DP1 receptor activation promotes PKA-mediated phosphorylation of Sp1, which upregulates NEDD4L expression; NEDD4L then ubiquitinates T-bet in CD4+ T cells, reducing Th1 cytokine-driven age-related hypertension. CD4+ T cell-specific KO mice, T-bet deletion, forced NEDD4L expression, co-immunoprecipitation, Western blot, blood pressure telemetry Circulation Medium 31893939
2016 NEDD4L directly interacts with and mediates K48-linked ubiquitination of SMAD2/SMAD3 (activated by TGF-β), targeting them for proteasomal degradation; this restrains TGF-β signal transduction. Co-immunoprecipitation, ubiquitination assay, TGF-β signaling assays (inferred from DDB2/NEDD4L functional study in ovarian cancer cells) Nucleic acids research Medium 26130719
2023 14-3-3σ promotes binding of S448-phosphorylated NEDD4L to HIF-1α, enhancing HIF-1α poly-ubiquitination and proteasomal degradation; NEDD4L acts as the E3 ligase in this 14-3-3σ-NEDD4L-HIF-1α axis. Co-immunoprecipitation, ubiquitination assay, phospho-site analysis, protein stability assay in CRC cells Cell reports Medium 37494179

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Yeast reveal a "druggable" Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons. Science (New York, N.Y.) 214 24158909
1997 The large subunit of RNA polymerase II is a substrate of the Rsp5 ubiquitin-protein ligase. Proceedings of the National Academy of Sciences of the United States of America 185 9108033
2005 14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase. The Journal of biological chemistry 155 15677482
2002 Concerted action of ENaC, Nedd4-2, and Sgk1 in transepithelial Na(+) transport. American journal of physiology. Renal physiology 155 12167587
1999 Functional domains of the Rsp5 ubiquitin-protein ligase. Molecular and cellular biology 151 9858558
2014 NEDD4-2 (NEDD4L): the ubiquitin ligase for multiple membrane proteins. Gene 147 25433090
1996 Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by human progesterone and glucocorticoid receptors. Molecular and cellular biology 140 8649367
2008 NEDD4L overexpression rescues the release and infectivity of human immunodeficiency virus type 1 constructs lacking PTAP and YPXL late domains. Journal of virology 139 18321968
2020 NEDD4L-mediated LTF protein degradation limits ferroptosis. Biochemical and biophysical research communications 138 32811647
2001 The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel. The Journal of biological chemistry 133 11244092
2004 Bsd2 binds the ubiquitin ligase Rsp5 and mediates the ubiquitination of transmembrane proteins. The EMBO journal 127 14988731
2005 The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme. The EMBO journal 126 15933713
2013 Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension. The Journal of clinical investigation 122 23348737
2013 The ART-Rsp5 ubiquitin ligase network comprises a plasma membrane quality control system that protects yeast cells from proteotoxic stress. eLife 114 23599894
2016 Mutations in the HECT domain of NEDD4L lead to AKT-mTOR pathway deregulation and cause periventricular nodular heterotopia. Nature genetics 96 27694961
2021 E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Nature communications 95 33608556
1996 Bul1, a new protein that binds to the Rsp5 ubiquitin ligase in Saccharomyces cerevisiae. Molecular and cellular biology 91 8668140
2008 Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain. The Biochemical journal 88 18498246
2006 The deubiquitinating enzyme Ubp2 modulates Rsp5-dependent Lys63-linked polyubiquitin conjugates in Saccharomyces cerevisiae. The Journal of biological chemistry 88 17028178
2017 Regulation of glutamate transporter trafficking by Nedd4-2 in a Parkinson's disease model. Cell death & disease 82 28151476
2008 Nedd4-2 induces endocytosis and degradation of proteolytically cleaved epithelial Na+ channels. The Journal of biological chemistry 82 18174164
2011 Respiratory distress and perinatal lethality in Nedd4-2-deficient mice. Nature communications 80 21505443
2023 circNEIL3 inhibits tumor metastasis through recruiting the E3 ubiquitin ligase Nedd4L to degrade YBX1. Proceedings of the National Academy of Sciences of the United States of America 74 36961927
2009 Rescue of DeltaF508-CFTR by the SGK1/Nedd4-2 signaling pathway. The Journal of biological chemistry 72 19617352
2004 The Rsp5 ubiquitin ligase binds to and ubiquitinates members of the yeast CIN85-endophilin complex, Sla1-Rvs167. The Journal of biological chemistry 71 14761940
2020 Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice. Nature communications 68 32332792
2000 Rsp5 WW domains interact directly with the carboxyl-terminal domain of RNA polymerase II. The Journal of biological chemistry 67 10781604
2013 NEDD4L is downregulated in colorectal cancer and inhibits canonical WNT signaling. PloS one 64 24312311
2018 Physiological Functions of Nedd4-2: Lessons from Knockout Mouse Models. Trends in biochemical sciences 62 30056838
2006 14-3-3 Mediates phosphorylation-dependent inhibition of the interaction between the ubiquitin E3 ligase Nedd4-2 and epithelial Na+ channels. Biochemistry 55 16716084
2022 LINC00941 promotes pancreatic cancer malignancy by interacting with ANXA2 and suppressing NEDD4L-mediated degradation of ANXA2. Cell death & disease 54 35977942
2018 A Tyrosine Switch on NEDD4-2 E3 Ligase Transmits GPCR Inflammatory Signaling. Cell reports 47 30232011
2007 NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity. Genes, brain, and behavior 46 17331106
2015 DDB2 modulates TGF-β signal transduction in human ovarian cancer cells by downregulating NEDD4L. Nucleic acids research 44 26130719
2020 USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L-SMAD pathway. Proceedings of the National Academy of Sciences of the United States of America 41 33106424
2014 In vivo regulation of NGF-mediated functions by Nedd4-2 ubiquitination of TrkA. The Journal of neuroscience : the official journal of the Society for Neuroscience 40 24760869
2005 Nedd4-2 isoforms differentially associate with ENaC and regulate its activity. American journal of physiology. Renal physiology 40 15814530
2022 ESR1 inhibits ionizing radiation-induced ferroptosis in breast cancer cells via the NEDD4L/CD71 pathway. Archives of biochemistry and biophysics 39 35613689
2017 NDFIP allows NEDD4/NEDD4L-induced AQP2 ubiquitination and degradation. PloS one 39 28931009
2008 Is the Rsp5 ubiquitin ligase involved in the regulation of ribophagy? Autophagy 39 18670191
2023 YAP Facilitates NEDD4L-Mediated Ubiquitination and Degradation of ACSL4 to Alleviate Ferroptosis in Myocardial Ischemia-Reperfusion Injury. The Canadian journal of cardiology 38 37541340
2015 NEDD4-2 and salt-sensitive hypertension. Current opinion in nephrology and hypertension 38 25602517
2022 CircKDM4B suppresses breast cancer progression via the miR-675/NEDD4L axis. Oncogene 37 35145234
2012 Sna3 is an Rsp5 adaptor protein that relies on ubiquitination for its MVB sorting. Traffic (Copenhagen, Denmark) 36 22212814
2016 The Nedd4-2/Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation. Nature communications 34 27786273
2023 NEDD4L facilitates granulosa cell ferroptosis by promoting GPX4 ubiquitination and degradation. Endocrine connections 33 36662677
2023 Cytoplasmic YAP1-mediated ESCRT-III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer. Cancer communications (London, England) 33 37005481
2016 Feedback modulation of neural network synchrony and seizure susceptibility by Mdm2-p53-Nedd4-2 signaling. Molecular brain 33 27000207
2017 Deletion of Nedd4-2 results in progressive kidney disease in mice. Cell death and differentiation 32 28862701
2019 Decreased expression of NEDD4L contributes to NSCLC progression and metastasis. Biochemical and biophysical research communications 31 30967264
2011 Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1. Journal of molecular and cellular cardiology 31 21463633
2001 Genetic interactions between the ESS1 prolyl-isomerase and the RSP5 ubiquitin ligase reveal opposing effects on RNA polymerase II function. Current genetics 31 11795843
2022 The Dual Regulation Effects of ESR1/NEDD4L on SLC7A11 in Breast Cancer Under Ionizing Radiation. Frontiers in cell and developmental biology 30 35252218
2020 DP1 Activation Reverses Age-Related Hypertension Via NEDD4L-Mediated T-Bet Degradation in T Cells. Circulation 30 31893939
2020 JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling. Theranostics 30 32724456
2016 Endoplasmic reticulum stress up-regulates Nedd4-2 to induce autophagy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 27022162
2004 Participation of the ubiquitin-conjugating enzyme UBE2E3 in Nedd4-2-dependent regulation of the epithelial Na+ channel. Molecular and cellular biology 30 14993279
2024 METTL3 regulates TFRC ubiquitination and ferroptosis through stabilizing NEDD4L mRNA to impact stroke. Cell biology and toxicology 29 38302612
2022 Paeoniflorin Regulates NEDD4L/STAT3 Pathway to Induce Ferroptosis in Human Glioma Cells. Journal of oncology 29 36618071
2018 Kir5.1 regulates Nedd4-2-mediated ubiquitination of Kir4.1 in distal nephron. American journal of physiology. Renal physiology 29 29897283
2017 Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion. Journal of the American Society of Nephrology : JASN 29 28289184
2003 Androgens differentially regulate the expression of NEDD4L transcripts in LNCaP human prostate cancer cells. Molecular and cellular endocrinology 29 14615060
2022 Research progress of Nedd4L in cardiovascular diseases. Cell death discovery 28 35429991
2021 Ubiquitinated ligation protein NEDD4L participates in MiR-30a-5p attenuated atherosclerosis by regulating macrophage polarization and lipid metabolism. Molecular therapy. Nucleic acids 28 34853729
2010 Nedd4-2 interacts with occludin to inhibit tight junction formation and enhance paracellular conductance in collecting duct epithelia. American journal of physiology. Renal physiology 28 20504882
2009 Nedd4-2-mediated ubiquitination facilitates processing of surfactant protein-C. American journal of respiratory cell and molecular biology 28 19423771
2021 Dexmedetomidine alleviates pulmonary edema through the epithelial sodium channel (ENaC) via the PI3K/Akt/Nedd4-2 pathway in LPS-induced acute lung injury. Immunologic research 27 33641076
2021 microRNA-454-mediated NEDD4-2/TrkA/cAMP axis in heart failure: Mechanisms and cardioprotective implications. Journal of cellular and molecular medicine 27 33949117
2017 The Ubiquitin Ligase Nedd4L Regulates the Na/K/2Cl Co-transporter NKCC1/SLC12A2 in the Colon. The Journal of biological chemistry 26 28087701
2016 Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli. Scientific reports 26 27604420
2011 Deubiquitylating enzyme USP2 counteracts Nedd4-2-mediated downregulation of KCNQ1 potassium channels. Heart rhythm 26 22024150
2009 G Protein Mono-ubiquitination by the Rsp5 Ubiquitin Ligase. The Journal of biological chemistry 26 19176477
2013 Pathobiological properties of the ubiquitin ligase Nedd4L in melanoma. International journal of experimental pathology 25 24456330
2002 PY motifs of Rod1 are required for binding to Rsp5 and for drug resistance. FEBS letters 25 12163175
2021 Non-SUMOylated CRMP2 decreases NaV1.7 currents via the endocytic proteins Numb, Nedd4-2 and Eps15. Molecular brain 24 33478555
2020 NEDD4L-mediated Merlin ubiquitination facilitates Hippo pathway activation. EMBO reports 24 33058421
2022 NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma. Cell death & disease 23 35236820
2022 E3 ubiquitin ligase NEDD4L negatively regulates inflammation by promoting ubiquitination of MEKK2. EMBO reports 23 36161689
2011 Yeast Rsp5 ubiquitin ligase affects the actin cytoskeleton in vivo and in vitro. European journal of cell biology 23 22000681
2023 NEDD4L inhibits migration, invasion, cisplatin resistance and promotes apoptosis of bladder cancer cells by inactivating the p62/Keap1/Nrf2 pathway. Environmental toxicology 22 37087754
2023 Inflammasome activation and metabolic remodelling in p16-positive aging cells aggravates high-fat diet-induced lung fibrosis by inhibiting NEDD4L-mediated K48-polyubiquitin-dependent degradation of SGK1. Clinical and translational medicine 22 37345264
2022 Downregulation of NEDD4L by EGFR signaling promotes the development of lung adenocarcinoma. Journal of translational medicine 22 35090513
2019 PLPP/CIN-mediated NEDD4-2 S448 dephosphorylation regulates neuronal excitability via GluA1 ubiquitination. Cell death & disease 22 31320629
2014 WNK3 abrogates the NEDD4-2-mediated inhibition of the renal Na+-Cl- cotransporter. American journal of physiology. Renal physiology 22 24920754
2021 E3 ubiquitin ligase NEDD4L negatively regulates keratinocyte hyperplasia by promoting GP130 degradation. EMBO reports 21 33769697
2020 Renal Tubule Nedd4-2 Deficiency Stimulates Kir4.1/Kir5.1 and Thiazide-Sensitive NaCl Cotransporter in Distal Convoluted Tubule. Journal of the American Society of Nephrology : JASN 21 32295826
2020 Piezo2 channel in nodose ganglia neurons is essential in controlling hypertension in a pathway regulated directly by Nedd4-2. Pharmacological research 20 33352230
2017 The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1. Development (Cambridge, England) 20 28246214
2023 14-3-3σ-NEDD4L axis promotes ubiquitination and degradation of HIF-1α in colorectal cancer. Cell reports 19 37494179
2022 A GID E3 ligase assembly ubiquitinates an Rsp5 E3 adaptor and regulates plasma membrane transporters. EMBO reports 19 35437932
2013 Ubp2 regulates Rsp5 ubiquitination activity in vivo and in vitro. PloS one 19 24069405
2023 A novel NEDD4L-TXNIP-CHOP axis in the pathogenesis of nonalcoholic steatohepatitis. Theranostics 18 37153733
2023 NEDD4L in human tumors: regulatory mechanisms and dual effects on anti-tumor and pro-tumor. Frontiers in pharmacology 18 38027016
2022 Elevated intracellular Na+ and osmolarity stimulate catalytic activity of the ubiquitin ligase Nedd4-2. Proceedings of the National Academy of Sciences of the United States of America 18 35858421
2021 FAT10 protects against ischemia-induced ventricular arrhythmia by decreasing Nedd4-2/Nav1.5 complex formation. Cell death & disease 18 33414395
2006 Rsp5 regulates expression of stress proteins via post-translational modification of Hsf1 and Msn4 in Saccharomyces cerevisiae. FEBS letters 18 16713599
2020 Deletion of ubiquitin ligase Nedd4l exacerbates ischemic brain damage. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 17 32703111
2015 The role of ubiquitin/Nedd4-2 in the pathogenesis of mesial temporal lobe epilepsy. Physiology & behavior 17 25700894
2012 Rsp5 ubiquitin ligase is required for protein trafficking in Saccharomyces cerevisiae COPI mutants. PloS one 17 22761830
2002 Substrate proteolysis is inhibited by dominant-negative Nedd4 and Rsp5 mutants harboring alterations in WW domain 1. Journal of cell science 17 11870222