Affinage

NEDD4L

E3 ubiquitin-protein ligase NEDD4-like · UniProt Q96PU5

Length
975 aa
Mass
111.9 kDa
Annotated
2026-06-10
100 papers in source corpus 50 papers cited in narrative 51 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NEDD4L (NEDD4-2) is a HECT-type E3 ubiquitin ligase that controls the surface abundance and activity of ion channels, transporters, receptors, and signaling proteins by catalyzing their ubiquitination, with UbcH5b serving as its primary E2 conjugating enzyme (PMID:16337426). Its WW domains engage PPxY (PY) motifs in substrates—paradigmatically all three ENaC subunits, where WW3 and WW4 contribute distinct non-interchangeable contacts—to drive substrate ubiquitination and endocytic/degradative removal from the cell surface (PMID:11244092, PMID:12424229, PMID:17502380). NEDD4L activity is gated by a multilayered phosphoregulatory network: SGK1 phosphorylates NEDD4-2 (at Ser444/Ser468 and related sites) to weaken WW-substrate engagement and recruit 14-3-3 proteins, which bind phospho-NEDD4-2 and impose a structural rearrangement that blocks intramolecular HECT-WW contacts and protects the phosphosites from dephosphorylation (PMID:11742982, PMID:11696533, PMID:15677482, PMID:16716084, PMID:34294877); conversely PLPP/CIN dephosphorylates Ser448 to license substrate ubiquitination (PMID:31320629), and GPCR/c-Src signaling phosphorylates Tyr485 to activate the ligase (PMID:30232011). An autoinhibitory intramolecular interaction between the WW domains and a PY motif in NEDD4-2's own HECT domain stabilizes the ligase and is relieved upon substrate binding, coupling target engagement to self-ubiquitination (PMID:18498246). Through these mechanisms NEDD4L is an essential in vivo regulator of renal and pulmonary sodium handling—targeting ENaC, the Na-Cl cotransporter NCC, and Kir4.1/Kir5.1—such that its loss causes salt-sensitive hypertension and defective lung fluid clearance (PMID:21505443, PMID:21852580, PMID:23348737, PMID:29897283). Beyond epithelial transport, NEDD4L ubiquitinates a broad substrate repertoire to shape neuronal excitability (GluA1, NaV channels) (PMID:28212375, PMID:24152020), innate and adaptive immune signaling (TRAF3, Syk, MEKK2, GP130) (PMID:33608556, PMID:27786273, PMID:36161689, PMID:33769697), and growth/stress pathways (PIK3CA, LGR5/DVL2, Merlin/NF2, SMAD2, TβRII, HIF-1α), often via adaptor- or scaffold-mediated substrate recruitment such as NDFIP1/2 and AMOTL1 (PMID:27339899, PMID:31867777, PMID:33058421, PMID:33106424, PMID:36257596, PMID:37494179, PMID:28931009). Epilepsy-associated missense mutations in NEDD4-2 disrupt GluA1 ubiquitination and alter seizure susceptibility, linking the ligase to neuronal disease (PMID:28212375).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    Establishing how a kinase signal is transduced into ion-channel abundance, SGK1 was shown to phosphorylate NEDD4-2 via a PY-motif interaction, weakening NEDD4-2/ENaC binding and raising channel surface expression — defining the core SGK1-NEDD4-2-ENaC regulatory axis.

    Evidence Co-IP, phosphosite mapping, in vitro kinase assay, and electrophysiology in Xenopus oocytes

    PMID:11696533 PMID:11742982

    Open questions at the time
    • Did not resolve the structural basis of phospho-dependent WW disengagement
    • Selectivity for hNedd4-2 over hNedd4 mechanistically unexplained at this stage
  2. 2001 Medium

    To define substrate recognition, the WW domains of NEDD4L were shown to bind PPxY motifs in all three ENaC subunits, with a dominant-negative WW construct disrupting Na+ feedback inhibition — establishing direct WW-PY engagement as the recognition mode.

    Evidence GST pulldown and whole-cell patch-clamp

    PMID:11244092

    Open questions at the time
    • Catalytic ubiquitination of ENaC not yet demonstrated
    • Relative contribution of individual WW domains unresolved
  3. 2002 Medium

    Refining the recognition map, WW3 and WW4 were shown to be the binding-competent domains contacting distinct non-interchangeable ENaC sites, both required for in vivo function.

    Evidence Surface plasmon resonance kinetics and patch-clamp

    PMID:12424229

    Open questions at the time
    • Structural identity of the two distinct ENaC sites not defined
    • Generality to non-ENaC substrates not tested
  4. 2005 High

    Explaining how the SGK1 signal is sustained, 14-3-3 proteins were found to bind SGK1-phosphorylated NEDD4-2 at Ser468, preserving stimulated ENaC current — adding a second tier of regulation.

    Evidence Co-IP, oocyte electrophysiology, surface biotinylation

    PMID:15677482 PMID:16716084

    Open questions at the time
    • Structural mechanism of 14-3-3 inhibition not yet resolved
    • Whether 14-3-3 acts on substrates beyond ENaC unknown
  5. 2007 High

    Confirming catalytic action, NEDD4-2 was shown to ubiquitinate cell-surface ENaC subunits — monoubiquitination sufficing to reduce surface current — with HECT activity required, establishing ubiquitination as the effector step.

    Evidence Ubiquitination assays, biotinylation, siRNA/overexpression, electrophysiology

    PMID:17502380

    Open questions at the time
    • Downstream endocytic/degradative machinery not defined
    • Ubiquitin chain linkage on ENaC not specified
  6. 2008 High

    Revealing intrinsic autoregulation, NEDD4-2 WW domains were found to bind an intramolecular HECT PY motif that suppresses auto-ubiquitination and stabilizes the ligase, with substrate binding disrupting this interaction — coupling target engagement to ligase turnover.

    Evidence Pulse-chase, Co-IP, mutagenesis, ubiquitination assays

    PMID:18498246

    Open questions at the time
    • Structural conformation of the autoinhibited state not resolved here
    • Interplay with 14-3-3 regulation not yet integrated
  7. 2011 High

    Testing physiological essentiality, Nedd4-2 knockout mice revealed that the ligase is required in vivo for ENaC-dependent fetal lung fluid clearance, with loss causing perinatal lethality and lung inflammation.

    Evidence Genetic knockout mouse, electrophysiology, immunoblotting

    PMID:21505443

    Open questions at the time
    • Tissue-specific contributions not dissected
    • Adult renal phenotype not addressed in this model
  8. 2011 High

    Extending substrate scope in the kidney, NEDD4-2 was shown to ubiquitinate NCC at the cell surface in a PY-motif-independent manner, with SGK1 antagonizing this regulation.

    Evidence Co-IP, ubiquitination assay, oocyte electrophysiology, biotinylation, KO mice

    PMID:21852580

    Open questions at the time
    • Recognition mode for the PY-independent NCC interaction undefined
    • Adaptor involvement not excluded
  9. 2013 High

    Defining the dominant renal target, nephron-specific inducible Nedd4-2 knockout produced thiazide-reversible salt-sensitive hypertension with elevated NCC, establishing NCC as a primary in vivo kidney substrate.

    Evidence Conditional KO mouse, immunoblotting, blood pressure telemetry, pharmacological rescue

    PMID:23348737

    Open questions at the time
    • Subunit-selective ENaC effects (β/γ but not α) mechanistically unexplained
    • Relative quantitative contribution of NCC vs ENaC not parsed
  10. 2018 High

    Identifying an activating modification, GPCR-driven c-Src phosphorylation of NEDD4-2 at Tyr485 was shown to switch on E3 ligase activity and downstream p38 signaling — a regulatory input opposite to inhibitory phosphorylation.

    Evidence MS phosphoproteomics, mutagenesis, kinase inhibitors, endothelial permeability assays

    PMID:30232011

    Open questions at the time
    • Direct substrate of the activated ligase in this context not fully defined
    • Structural effect of Y485 phosphorylation unresolved
  11. 2021 High

    Providing the structural basis of inhibition, integrative structural biology showed 14-3-3 binding to phospho-Ser342/Ser448 rearranges NEDD4-2 to block intramolecular HECT-WW contacts, unifying the phospho/14-3-3 and autoinhibition models.

    Evidence SAXS, NMR, HDX-MS, mutagenesis, phosphopeptide binding

    PMID:34294877

    Open questions at the time
    • High-resolution structure of the full assembly absent
    • How substrate engagement competes with 14-3-3 not directly visualized

Open questions

Synthesis pass · forward-looking unresolved questions
  • Broadening to channels, transporters, and signaling, NEDD4L was shown across studies to ubiquitinate Nav channels, hERG1, OAT3, Kir4.1/Kir5.1, GluA1, SP-C, AQP2, and to regulate immune and growth pathways via TRAF3, Syk, MEKK2, GP130, PIK3CA, LGR5/DVL2, Merlin/NF2, SMAD2, TβRII, HIF-1α and ferroptosis regulators.
  • Many substrate interactions rest on single-laboratory Co-IP/ubiquitination data
  • Ubiquitin chain linkages and adaptor requirements differ across substrates and are incompletely mapped
  • Whether the diverse single-study substrate and ferroptosis-related claims reflect a unified mechanism or context-specific regulation, and which substrates dominate each physiological setting, remains unresolved.
  • Many ferroptosis substrates (GPX4, ACSL4, STAT3, ENO1, YBX1) rest on Low-confidence single Co-IPs
  • In vivo substrate hierarchy outside kidney/lung not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016874 ligase activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-382551 Transport of small molecules 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-112316 Neuronal System 3
Partners
AMOTL1GRK2NDFIP1SCNN1ASGK1SLC12A3USP7YWHAB

Evidence

Reading pass · 51 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 SGK1 phosphorylates Nedd4-2 on Ser444 (and to a lesser extent Ser338) via a PY motif-dependent interaction, reducing the interaction between Nedd4-2 and ENaC and thereby increasing ENaC cell surface expression. Expression studies in Xenopus laevis oocytes, co-immunoprecipitation, phosphorylation mapping The EMBO journal High 11742982
2001 SGK1 binds to hNedd4-2 via a PY motif in SGK1 and phosphorylates hNedd4-2 (but not hNedd4), reducing hNedd4-2 binding to αENaC and thereby relieving hNedd4-2-mediated inhibition of Na+ absorption. Co-immunoprecipitation, in vitro phosphorylation assay, electrophysiology in Xenopus oocytes The Journal of biological chemistry High 11696533
2001 KIAA0439 (NEDD4L/Nedd4-2) WW domains bind all three ENaC subunits (α, β, γ) via PPxY motifs; a recombinant dominant-negative WW domain construct interferes with Na+-dependent feedback inhibition of ENaC in whole-cell patch-clamp experiments. GST pulldown, whole-cell patch-clamp electrophysiology The Journal of biological chemistry Medium 11244092
2002 Only WW3 and WW4 domains of Nedd4-2 are required for both binding to ENaC subunits and regulation of Na+ feedback control; both domains together are essential for in vivo function, indicating they interact with distinct non-interchangeable sites in ENaC. Surface plasmon resonance binding kinetics, whole-cell patch-clamp in mammalian cells, Xenopus oocyte expression FASEB journal Medium 12424229
2005 14-3-3 proteins bind directly to SGK1-phosphorylated Nedd4-2 at Ser-468, preserving the activity of SGK1-stimulated ENaC-dependent Na+ current; disrupting the 14-3-3/Nedd4-2 interaction decreases ENaC surface density, likely by allowing Nedd4-2-mediated ubiquitination and ENaC degradation. Co-immunoprecipitation, Xenopus oocyte electrophysiology, surface biotinylation The Journal of biological chemistry High 15677482
2006 14-3-3 proteins inhibit the interaction between WW domains of hNedd4-2 and the PY motif of ENaC in a manner dependent on SGK1-catalyzed phosphorylation of Ser468 (and similarly PKA-mediated phosphorylation), shielding phosphorylated Nedd4-2 from dephosphorylation. Surface plasmon resonance spectrometry, Xenopus oocyte electrophysiology Biochemistry High 16716084
2007 Nedd4-2 catalyzes ubiquitination of α-, β-, and γENaC subunits at the cell surface; monoubiquitination is sufficient to reduce ENaC surface expression and current; HECT domain mutation abolishes activity; Nedd4-2 selectively reduces surface ENaC without affecting immature biosynthetic ENaC. Ubiquitination assays, surface biotinylation, siRNA knockdown, overexpression, electrophysiology The Journal of biological chemistry High 17502380
2008 The WW domains of Nedd4-2 bind an intramolecular PY motif (LPXY) within its own HECT domain, inhibiting auto-ubiquitination and stabilizing Nedd4-2; mutation of this HECT PY motif decreases Nedd4-2 stability without affecting ENaC ubiquitination; ENaC binding disrupts this intramolecular interaction, triggering Nedd4-2 self-ubiquitination and degradation. Pulse-chase experiments, co-immunoprecipitation, mutational analysis, ubiquitination assays The Biochemical journal High 18498246
2004 GRK2 phosphorylates the C terminus of the ENaC β subunit and renders ENaC insensitive to inhibition by Nedd4-2, maintaining channels in the active state; this represents a mechanism by which GRK2 counteracts Nedd4-2-dependent channel inhibition. Xenopus oocyte electrophysiology, in vitro kinase assay, epistasis experiments Proceedings of the National Academy of Sciences of the United States of America Medium 15284439
2007 GRK2 physically interacts with both Nedd4 and Nedd4-2, and phosphorylates both ligases at multiple sites including Thr466 in the WW3 domain region of Nedd4. Co-immunoprecipitation, in vitro phosphorylation assay Biochemical and biophysical research communications Medium 17544362
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; surviving knockouts develop lethal sterile lung inflammation, establishing Nedd4-2 as an essential regulator of ENaC-dependent lung fluid clearance in vivo. Genetic knockout mouse model, electrophysiology, immunoblotting Nature communications High 21505443
2011 Nedd4-2 co-immunoprecipitates with NCC and stimulates NCC ubiquitylation at the cell surface; catalytically inactive Nedd4-2 fails to decrease NCC activity; SGK1 prevents this inhibition in a kinase-dependent manner; double phosphorylation of Nedd4-2 at Ser222/Ser328 abolishes SGK1-mediated rescue. Unlike ENaC regulation, this does not require a PY motif in NCC. Co-immunoprecipitation, ubiquitination assay, Xenopus oocyte electrophysiology, surface biotinylation, knockout mice Journal of the American Society of Nephrology High 21852580
2013 Inducible, nephron-specific Nedd4-2 knockout in mice causes salt-sensitive hypertension characterized by increased NCC, β/γENaC (but not αENaC) and ROMK expression; thiazide treatment reverses hypertension, demonstrating NCC as a primary in vivo target of NEDD4-2 in the kidney. Conditional knockout mouse model, immunoblotting, blood pressure telemetry, pharmacological rescue The Journal of clinical investigation High 23348737
2014 Nedd4-2 regulates voltage-gated sodium channel (Nav) activity specifically in response to elevated intracellular Na+ in fetal cortical neurons but does not affect steady-state Nav activity, as shown using Nedd4-2-deficient mice; no such regulation was observed in dorsal root ganglia neurons from the same mice. Nedd4-2 knockout mouse neurons, electrophysiology, intracellular Na+ manipulation The Biochemical journal Medium 24152020
2016 NEDD4-2 ubiquitinates TRAF3 at Cys56 and Cys124 (zinc finger residues) via K29-linked cysteine ubiquitination; this promotes enhanced TRAF3 association with K48/K63 E3 ligases (cIAP1/2, HECTD3) and TRAF3-TBK1 interaction, leading to TBK1 and IRF3 phosphorylation and type I interferon production upon virus infection. Co-immunoprecipitation, ubiquitination assay, mass spectrometry, site-directed mutagenesis, knockout cells and mice Nature communications High 33608556
2017 Nedd4-2 ubiquitinates and downregulates the cardiac potassium channel hERG1 via a PY motif in the C-terminus of hERG1; Nedd4-2 co-expression decreases total and surface hERG1 protein and whole-cell current; deletion of the PY motif abrogates Nedd4-2-dependent regulation. Co-immunoprecipitation, surface biotinylation, Western blot, electrophysiology in HEK293 cells Journal of molecular and cellular cardiology Medium 21463633
2017 Nedd4-2 ubiquitinates and decreases surface expression and activity of organic anion transporter OAT3; this requires the WW3 and WW4 domains of Nedd4-2; a physical interaction between OAT3 and Nedd4-2 was confirmed in cultured cells and rat kidney slices. Co-immunoprecipitation, ubiquitination assay, transport activity assay, siRNA knockdown, mutagenesis Molecular pharmaceutics Medium 26651153
2017 NEDD4L binds to and promotes ubiquitination and proteasome-dependent degradation of PIK3CA (p110α catalytic subunit of PI3K), negatively regulating PIK3CA protein levels and affecting PI3K-AKT signaling; NEDD4L does not ubiquitinate the PI3K regulatory subunit. Co-immunoprecipitation, ubiquitination assay, cycloheximide chase, overexpression/knockdown with immunoblotting The Journal of biological chemistry Medium 27339899
2017 Nedd4-2 ubiquitinates phosphorylated Syk (a tyrosine kinase essential for FcɛRI signaling) with adaptor protein Ndfip1, limiting the intensity and duration of IgE-FcɛRI signaling in mast cells; loss of Nedd4-2 or Ndfip1 in mast cells causes exacerbated cutaneous anaphylaxis in vivo. Co-immunoprecipitation, ubiquitination assay, mast cell-specific knockout mice, in vivo anaphylaxis model Nature communications High 27786273
2018 GPCR PAR1 stimulates c-Src-mediated tyrosine phosphorylation of NEDD4-2 at Y485 (within the linker between WW2 and WW3 domains), activating NEDD4-2 E3 ligase activity and driving p38 signaling and endothelial barrier disruption; Y485 mutation impairs E3 ligase activity and p38 activation. Mass spectrometry phosphoproteomics, site-directed mutagenesis, kinase inhibitor experiments, endothelial permeability assays Cell reports High 30232011
2018 Nedd4-2 binds to Kir5.1 via a phosphothreonine (TPVT) motif at its C-terminus; this interaction facilitates ubiquitination of the Kir4.1/Kir5.1 heterotetramer (not Kir4.1 alone) and reduces Kir4.1 expression and K+ currents in the distal convoluted tubule. Co-immunoprecipitation, GST pulldown, ubiquitination assay, patch-clamp electrophysiology, Kir5.1 mutagenesis, kidney-specific Nedd4-2 knockout mice American journal of physiology. Renal physiology High 29897283
2019 NEDD4L binds ULK1 in pancreatic cancer cells and promotes its ubiquitination and degradation; NEDD4L depletion stabilizes ULK1, enhancing autophagy activity and mitochondrial metabolic function; NEDD4L also regulates the glutamine transporter ASCT2. Co-immunoprecipitation, siRNA knockdown, immunoblotting, oxygen consumption rate measurement, xenograft mouse models Cell death & disease Medium 31959741
2019 NEDD4 and NEDD4L negatively regulate Wnt/β-catenin signaling by targeting LGR5 receptor and DVL2 for proteasomal and lysosomal degradation; loss of both ligases enhances ISC proliferation, increases RSPO sensitivity, and accelerates tumor development in Apcmin mice. Conditional knockout mice, co-immunoprecipitation, ubiquitination assay, organoid culture, tumor phenotyping The EMBO journal Medium 31867777
2020 NEDD4L identifies and promotes ubiquitination and proteasomal degradation of lactotransferrin (LTF) via direct protein-protein interaction, thereby inhibiting intracellular iron accumulation and ferroptotic cell death. siRNA screen, mass spectrometry for substrate identification, co-immunoprecipitation, ubiquitination assay, ferroptosis cell death assays Biochemical and biophysical research communications Medium 32811647
2020 NEDD4L ubiquitinates and promotes degradation of SMAD2, a TGFβ pathway transcription modulator; USP7 deubiquitinates NEDD4L (stabilizing it), and this USP7-NEDD4L-SMAD2 axis controls autophagy and protein quality control in a neuroprotective pathway conserved from C. elegans to mammals. Genetic epistasis in C. elegans and Drosophila, co-immunoprecipitation, ubiquitination assay in mammalian cells Proceedings of the National Academy of Sciences of the United States of America Medium 33106424
2020 NEDD4-2 ubiquitinates α-synuclein after focal ischemia; Nedd4l knockout reduces post-ischemic poly-ubiquitinated α-synuclein and exacerbates ischemic brain damage; co-immunoprecipitation confirms enhanced α-synuclein–Nedd4l interaction after stroke. Transient MCAO mouse model, knockout mice, co-immunoprecipitation, behavioral testing Journal of cerebral blood flow and metabolism Medium 32703111
2020 NEDD4-2 mediates ubiquitination and degradation of Merlin/NF2 (mostly mono/di-ubiquitination at K396); this requires the scaffold protein AMOTL1 to bridge NEDD4L to Merlin; ubiquitination is promoted by Ser518 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, Ca2+ signaling experiments, Lats1 kinase activity assay EMBO reports Medium 33058421
2017 Nedd4-2 ubiquitinates the SP-C proprotein at K6 (via its PY motif binding to Nedd4-2 WW domains), and this ubiquitination is required for lumenal relocation of SP-C within multivesicular bodies, leading to SP-C processing and secretion. GST pulldown with recombinant proteins, co-immunoprecipitation, ubiquitination assay, alanine mutagenesis, adenoviral infection in type II cells American journal of respiratory cell and molecular biology Medium 19423771
2017 NDFIP2 (and NDFIP1) serve as adaptors that bridge NEDD4/NEDD4L to AQP2, enabling NEDD4/NEDD4L-mediated ubiquitination and degradation of AQP2; NEDD4 and NEDD4L do not bind AQP2 directly. Membrane Yeast Two-Hybrid, siRNA knockdown, co-immunoprecipitation, ubiquitination assay, immunoblotting in HEK293 and mpkCCD cells PloS one Medium 28931009
2017 Nedd4-2 ubiquitinates epilepsy-associated GluA1 subunit of AMPA receptors, reducing GluA1 surface expression; epilepsy-associated missense mutations in Nedd4-2 disrupt GluA1 ubiquitination; genetic reduction of GluA1 normalizes seizure susceptibility in Nedd4-2andi mice. Knockout/knock-in mouse model, ubiquitination assay, surface biotinylation, extracellular electrophysiology, in vivo seizure model, genetic epistasis PLoS genetics High 28212375
2021 14-3-3 protein binding to phosphorylated Ser342 and Ser448 of Nedd4-2 induces a structural rearrangement that inhibits intramolecular interactions between the HECT and WW domains, providing the structural basis for 14-3-3-mediated Nedd4-2 regulation. Integrative structural biology (SAXS, NMR, HDX-MS), mutagenesis, phosphopeptide binding assays Communications biology High 34294877
2019 PLPP/CIN (pyridoxal-5'-phosphate phosphatase/chronophin) specifically dephosphorylates NEDD4-2 at Ser448, reducing Nedd4-2 ubiquitination and facilitating NEDD4-2-mediated ubiquitination of GluA1, thereby modulating neuronal excitability. In vitro phosphatase assay, co-immunoprecipitation, ubiquitination assay, electrophysiology, knockout cell models Cell death & disease Medium 31320629
2022 NEDD4L directly interacts with MEKK2 and promotes its poly-ubiquitination and degradation; IL-17-induced Ser520 phosphorylation of MEKK2 is required for NEDD4L-mediated MEKK2 degradation and shutdown of IL-17R signaling; Nedd4l-deficient mice show increased susceptibility to IL-17-induced inflammation. Co-immunoprecipitation, ubiquitination assay, mutagenesis, knockout mice, experimental autoimmune encephalomyelitis (EAE) model EMBO reports High 36161689
2022 NEDD4L directly interacts with GP130 and mediates its Lys-27-linked ubiquitination and proteasomal degradation, negatively regulating IL-6/GP130/STAT3 signaling in keratinocytes and suppressing skin hyperplasia. Co-immunoprecipitation, ubiquitination assay, mutagenesis, knockout mice (imiquimod skin model), immunohistochemistry EMBO reports Medium 33769697
2022 NEDD4L directly interacts with GPX4 and promotes its ubiquitination and degradation, facilitating ferroptosis in granulosa cells. Co-immunoprecipitation, ubiquitination assay, cell viability assay, ferroptosis marker measurement Endocrine connections Low 36662677
2022 NEDD4L promotes ubiquitination and degradation of ENO1 (enolase 1), suppressing glycolysis and proliferation in oral squamous cell carcinoma; ENO1 overexpression reverses functional effects of NEDD4L overexpression. Ubiquitination assay, co-immunoprecipitation, overexpression/knockdown with glycolysis measurements, in vivo tumor model Cancer biology & therapy Low 35316145
2023 NEDD4L mediates ubiquitination and degradation of YBX1 protein when recruited by circNEIL3; direct interaction between NEDD4L and YBX1 was confirmed, and this promotes proteasomal degradation of YBX1 to suppress tumor metastasis. Co-immunoprecipitation, ubiquitination assay, loss-of-function/overexpression experiments in cancer cells and in vivo Proceedings of the National Academy of Sciences of the United States of America Low 36961927
2023 NEDD4L ubiquitinates and degrades ACSL4, a key ferroptosis regulator; YAP facilitates NEDD4L transcription, so YAP→NEDD4L→ACSL4 ubiquitination axis reduces ferroptosis in myocardial ischemia-reperfusion injury. Co-immunoprecipitation, ChIP, dual-luciferase reporter assay, Western blot, in vivo MIRI model The Canadian journal of cardiology Low 37541340
2023 14-3-3σ promotes binding of S448-phosphorylated NEDD4L to HIF-1α, enhancing HIF-1α poly-ubiquitination and proteasomal degradation; this suppresses hypoxia-induced tumor progression in colorectal cancer. Co-immunoprecipitation, ubiquitination assay, mutagenesis, patient sample correlation analysis Cell reports Medium 37494179
2024 NEDD4L ubiquitinates and degrades TFRC (transferrin receptor/CD71), reducing iron accumulation; METTL3-mediated m6A methylation stabilizes NEDD4L mRNA, enhancing NEDD4L expression and the NEDD4L-TFRC axis to inhibit ferroptosis and neuronal damage in ischemic stroke. Co-immunoprecipitation, ubiquitination assay, half-life experiments, MCAO mouse model, NEDD4L knockout model Cell biology and toxicology Medium 38302612
2021 Non-SUMOylated CRMP2 forms a complex with Numb, Eps15, and Nedd4-2 to promote clathrin-mediated endocytosis of NaV1.7; silencing Nedd4-2 in DRG neurons from CRMP2K374A/K374A mice restores NaV1.7 surface expression and sodium currents. siRNA knockdown in DRG neurons, electrophysiology, in vivo nerve injury model Molecular brain Medium 33478555
2020 NEDD4L interacts with Piezo2 in co-immunoprecipitation experiments in HEK293T cells and inhibits Piezo2 mechanically-activated currents when co-expressed; Nedd4-2 upregulation in hypertensive rat nodose ganglia correlates with Piezo2 downregulation. Co-immunoprecipitation, electrophysiology in HEK293T, in vivo knockdown, spontaneously hypertensive rat model Pharmacological research Low 33352230
2023 NEDD4L deficiency in intestinal epithelial cells inhibits expression of SLC3A2 (protein level only, not mRNA), reducing GPX4 expression and promoting ferroptosis; this mechanistic axis (NEDD4L→SLC3A2→GPX4) maintains intestinal homeostasis and restricts inflammatory bowel disease. Conditional and global KO mice, DSS/TNBS colitis and AOM-DSS tumor models, immunoblotting, ferroptosis inhibitor rescue The Journal of clinical investigation Medium 39688910
2005 Both Nedd4 and Nedd4-2 use UbcH5b as their primary E2 ubiquitin-conjugating enzyme in in vitro ubiquitination assays; Ube2e3 is used less efficiently by both. In vitro ubiquitination assay with panel of E2 enzymes The international journal of biochemistry & cell biology Medium 16337426
2009 NEDD4L directly binds surfactant protein-C (SP-C) proprotein via interaction of its WW domain with the PPDY motif in SP-C residues 12-17; NEDD4L ubiquitinates SP-C at K6 (but not K34); this ubiquitination is required for SP-C proprotein processing. GST pulldown with recombinant proteins, endogenous Co-IP from lung lysates, ubiquitination assay, mutagenesis, SP-C secretion assay American journal of respiratory cell and molecular biology Medium 19423771
2016 NEDD4L overexpression up-regulates autophagy; knockdown suppresses both basal and ER stress-induced autophagy in cultured cells; Nedd4-2 expression is induced by ER stress via IRE1/XBP1s pathway, linking UPR to autophagic response. Pharmacological ER stress induction, siRNA knockdown, overexpression, IRE1 inhibition, immunoblotting for autophagy markers FASEB journal Low 27022162
2023 Decreased NEDD4L expression leads to impaired TXNIP ubiquitination and its accumulation in NASH liver; NEDD4L-mediated TXNIP degradation is part of a NEDD4L-TXNIP-CHOP axis that controls hepatocyte apoptosis in nonalcoholic steatohepatitis. Four independent NASH mouse models, gain/loss-of-function studies, co-immunoprecipitation, ubiquitination assay Theranostics Medium 37153733
2023 NEDD4L mediates ubiquitination and degradation of STAT3, as shown by co-immunoprecipitation in glioma cells; NEDD4L-induced ferroptosis is rescued by forced expression of STAT3, placing STAT3 downstream of NEDD4L in glioma ferroptosis regulation. Co-immunoprecipitation, ubiquitination assay, genetic rescue experiments, xenograft mouse model Journal of oncology Low 36618071
2022 NEDD4L binds the 19S proteasome and promotes autophagy; NEDD4L suppression reduces bortezomib sensitivity in multiple myeloma through autophagy inhibition. Co-immunoprecipitation with proteasome components, knockdown with autophagy and viability assays, in vivo mouse model Cell death & disease Low 35236820
2023 NEDD4L ubiquitinates and degrades TβRII (TGF-β receptor II), the first signaling enzyme of TGF-β1 pathway, suppressing lung myofibroblast differentiation; transcription factor E2F inhibits NEDD4L expression, and blocking E2F rescues NEDD4L levels and mitigates experimental pulmonary fibrosis. Co-immunoprecipitation, ubiquitination assay, knockdown/overexpression, E2F inhibitor experiments, animal model of pulmonary fibrosis Translational research Medium 36257596
2023 NEDD4L mediates ubiquitination and degradation of ACE2 in neurogenic hypertension; Ang-II-induced upregulation of Nedd4-2 in the brain promotes ACE2 ubiquitination; mutation of lysine residues in the ACE2 C-terminus confers ubiquitination resistance. Co-immunoprecipitation, ubiquitination assay, mutagenesis, gene therapy in brain regions, blood pressure telemetry Cardiovascular research Medium 37161607

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression. The EMBO journal 570 11742982
2001 Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel. The Journal of biological chemistry 357 11696533
2010 Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions. Cell death and differentiation 194 19557014
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 186 9108033
2007 Nedd4-2 catalyzes ubiquitination and degradation of cell surface ENaC. The Journal of biological chemistry 179 17502380
2014 Rsp5/Nedd4 is the main ubiquitin ligase that targets cytosolic misfolded proteins following heat stress. Nature cell biology 157 25344756
2002 Concerted action of ENaC, Nedd4-2, and Sgk1 in transepithelial Na(+) transport. American journal of physiology. Renal physiology 156 12167587
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
2014 NEDD4-2 (NEDD4L): the ubiquitin ligase for multiple membrane proteins. Gene 149 25433090
2011 Nedd4-2 modulates renal Na+-Cl- cotransporter via the aldosterone-SGK1-Nedd4-2 pathway. Journal of the American Society of Nephrology : JASN 141 21852580
2020 NEDD4L-mediated LTF protein degradation limits ferroptosis. Biochemical and biophysical research communications 139 32811647
2001 The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel. The Journal of biological chemistry 133 11244092
2005 The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme. The EMBO journal 126 15933713
2001 Domains of the Rsp5 ubiquitin-protein ligase required for receptor-mediated and fluid-phase endocytosis. Molecular biology of the cell 124 11179425
2013 Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension. The Journal of clinical investigation 122 23348737
2021 E3 ligase Nedd4l promotes antiviral innate immunity by catalyzing K29-linked cysteine ubiquitination of TRAF3. Nature communications 97 33608556
2008 Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain. The Biochemical journal 89 18498246
2006 The deubiquitinating enzyme Ubp2 modulates Rsp5-dependent Lys63-linked polyubiquitin conjugates in Saccharomyces cerevisiae. The Journal of biological chemistry 88 17028178
2020 NEDD4L downregulates autophagy and cell growth by modulating ULK1 and a glutamine transporter. Cell death & disease 86 31959741
2002 The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 84 12424229
2019 NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor. The EMBO journal 82 31867777
2011 Respiratory distress and perinatal lethality in Nedd4-2-deficient mice. Nature communications 81 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 78 36961927
2012 Nedd4-2 and the regulation of epithelial sodium transport. Frontiers in physiology 73 22737130
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
2004 The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels. Proceedings of the National Academy of Sciences of the United States of America 69 15284439
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 63 30056838
2017 Epilepsy-associated gene Nedd4-2 mediates neuronal activity and seizure susceptibility through AMPA receptors. PLoS genetics 59 28212375
2006 14-3-3 Mediates phosphorylation-dependent inhibition of the interaction between the ubiquitin E3 ligase Nedd4-2 and epithelial Na+ channels. Biochemistry 56 16716084
2012 Nedd4 and Nedd4-2: ubiquitin ligases at work in the neuron. The international journal of biochemistry & cell biology 51 23262292
2001 NEDD4L on human chromosome 18q21 has multiple forms of transcripts and is a homologue of the mouse Nedd4-2 gene. European journal of human genetics : EJHG 50 11840194
2018 A Tyrosine Switch on NEDD4-2 E3 Ligase Transmits GPCR Inflammatory Signaling. Cell reports 49 30232011
2007 NEDD4-2 as a potential candidate susceptibility gene for epileptic photosensitivity. Genes, brain, and behavior 46 17331106
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 43 33106424
2022 ESR1 inhibits ionizing radiation-induced ferroptosis in breast cancer cells via the NEDD4L/CD71 pathway. Archives of biochemistry and biophysics 41 35613689
2021 14-3-3-protein regulates Nedd4-2 by modulating interactions between HECT and WW domains. Communications biology 41 34294877
2016 NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling. The Journal of biological chemistry 41 27339899
2023 YAP Facilitates NEDD4L-Mediated Ubiquitination and Degradation of ACSL4 to Alleviate Ferroptosis in Myocardial Ischemia-Reperfusion Injury. The Canadian journal of cardiology 40 37541340
2005 Nedd4-2 isoforms differentially associate with ENaC and regulate its activity. American journal of physiology. Renal physiology 40 15814530
2004 NPR1 kinase and RSP5-BUL1/2 ubiquitin ligase control GLN3-dependent transcription in Saccharomyces cerevisiae. The Journal of biological chemistry 40 15247235
2017 NDFIP allows NEDD4/NEDD4L-induced AQP2 ubiquitination and degradation. PloS one 39 28931009
2022 CircKDM4B suppresses breast cancer progression via the miR-675/NEDD4L axis. Oncogene 38 35145234
2015 NEDD4-2 and salt-sensitive hypertension. Current opinion in nephrology and hypertension 38 25602517
2022 NEDD4L inhibits glycolysis and proliferation of cancer cells in oral squamous cell carcinoma by inducing ENO1 ubiquitination and degradation. Cancer biology & therapy 37 35316145
2023 Cytoplasmic YAP1-mediated ESCRT-III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer. Cancer communications (London, England) 35 37005481
2016 The Nedd4-2/Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation. Nature communications 35 27786273
2017 Deletion of Nedd4-2 results in progressive kidney disease in mice. Cell death and differentiation 34 28862701
2024 METTL3 regulates TFRC ubiquitination and ferroptosis through stabilizing NEDD4L mRNA to impact stroke. Cell biology and toxicology 33 38302612
2023 NEDD4L facilitates granulosa cell ferroptosis by promoting GPX4 ubiquitination and degradation. Endocrine connections 33 36662677
2020 JP1 suppresses proliferation and metastasis of melanoma through MEK1/2 mediated NEDD4L-SP1-Integrin αvβ3 signaling. Theranostics 32 32724456
2014 Nedd4-2 (NEDD4L) controls intracellular Na(+)-mediated activity of voltage-gated sodium channels in primary cortical neurons. The Biochemical journal 32 24152020
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 Paeoniflorin Regulates NEDD4L/STAT3 Pathway to Induce Ferroptosis in Human Glioma Cells. Journal of oncology 30 36618071
2018 Kir5.1 regulates Nedd4-2-mediated ubiquitination of Kir4.1 in distal nephron. American journal of physiology. Renal physiology 30 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 30 28289184
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
2023 Nedd4-2 up-regulation is associated with ACE2 ubiquitination in hypertension. Cardiovascular research 29 37161607
2009 Nedd4-2-mediated ubiquitination facilitates processing of surfactant protein-C. American journal of respiratory cell and molecular biology 29 19423771
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 microRNA-454-mediated NEDD4-2/TrkA/cAMP axis in heart failure: Mechanisms and cardioprotective implications. Journal of cellular and molecular medicine 27 33949117
2018 The Role of Intercalated Cell Nedd4-2 in BP Regulation, Ion Transport, and Transporter Expression. Journal of the American Society of Nephrology : JASN 26 29773687
2018 Rsp5 Ubiquitin ligase-mediated quality control system clears membrane proteins mistargeted to the vacuole membrane. The Journal of cell biology 26 30361468
2016 Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli. Scientific reports 26 27604420
2015 An Essential Role of Nedd4-2 in the Ubiquitination, Expression, and Function of Organic Anion Transporter-3. Molecular pharmaceutics 26 26651153
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
2020 NEDD4L-mediated Merlin ubiquitination facilitates Hippo pathway activation. EMBO reports 25 33058421
2007 GRK2 interacts with and phosphorylates Nedd4 and Nedd4-2. Biochemical and biophysical research communications 25 17544362
2005 The ubiquitin-protein ligases Nedd4 and Nedd4-2 show similar ubiquitin-conjugating enzyme specificities. The international journal of biochemistry & cell biology 25 16337426
2022 NEDD4L binds the proteasome and promotes autophagy and bortezomib sensitivity in multiple myeloma. Cell death & disease 24 35236820
2022 E3 ubiquitin ligase NEDD4L negatively regulates inflammation by promoting ubiquitination of MEKK2. EMBO reports 24 36161689
2021 Non-SUMOylated CRMP2 decreases NaV1.7 currents via the endocytic proteins Numb, Nedd4-2 and Eps15. Molecular brain 24 33478555
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 23 37345264
2019 PLPP/CIN-mediated NEDD4-2 S448 dephosphorylation regulates neuronal excitability via GluA1 ubiquitination. Cell death & disease 23 31320629
2011 Yeast Rsp5 ubiquitin ligase affects the actin cytoskeleton in vivo and in vitro. European journal of cell biology 23 22000681
2005 Rsp5 ubiquitin ligase modulates translation accuracy in yeast Saccharomyces cerevisiae. RNA (New York, N.Y.) 23 16177134
2022 Downregulation of NEDD4L by EGFR signaling promotes the development of lung adenocarcinoma. Journal of translational medicine 22 35090513
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 22 32295826
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 Piezo2 channel in nodose ganglia neurons is essential in controlling hypertension in a pathway regulated directly by Nedd4-2. Pharmacological research 21 33352230
2024 NEDD4L mediates intestinal epithelial cell ferroptosis to restrict inflammatory bowel diseases and colorectal tumorigenesis. The Journal of clinical investigation 20 39688910
2023 A novel NEDD4L-TXNIP-CHOP axis in the pathogenesis of nonalcoholic steatohepatitis. Theranostics 20 37153733
2022 A GID E3 ligase assembly ubiquitinates an Rsp5 E3 adaptor and regulates plasma membrane transporters. EMBO reports 20 35437932
2020 An outlined review for the role of Nedd4-1 and Nedd4-2 in lung disorders. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20 32092816
2019 Mg2+ restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia. American journal of physiology. Renal physiology 20 31364380
2017 The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1. Development (Cambridge, England) 20 28246214
2017 PKC/Nedd4-2 Signaling Pathway Regulates the Cell Surface Expression of Drug Transporter hOAT1. Drug metabolism and disposition: the biological fate of chemicals 20 28572241
2005 Transcriptional diversity and expression of NEDD4L gene in distal nephron. Biochemical and biophysical research communications 20 16338225
2023 14-3-3σ-NEDD4L axis promotes ubiquitination and degradation of HIF-1α in colorectal cancer. Cell reports 19 37494179
2023 NEDD4L in human tumors: regulatory mechanisms and dual effects on anti-tumor and pro-tumor. Frontiers in pharmacology 19 38027016
2015 Nedd4L expression is decreased in ovarian epithelial cancer tissues compared to ovarian non-cancer tissue. The journal of obstetrics and gynaecology research 19 26554540
2013 Ubp2 regulates Rsp5 ubiquitination activity in vivo and in vitro. PloS one 19 24069405
2022 Nedd4L suppression in lung fibroblasts facilitates pathogenesis of lung fibrosis. Translational research : the journal of laboratory and clinical medicine 18 36257596
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 18 32703111

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