Gene Symbol: Nedd4l
Description: neural precursor cell expressed, developmentally down-regulated gene 4-like
Alias: 1300012C07Rik, Nedd4-2, Nedd4b, E3 ubiquitin-protein ligase NEDD4-like, HECT-type E3 ubiquitin transferase NED4L, NEDD4.2, neural precursor cell expressed, developmentally down-regulated gene 4b
Species: mouse
Products:     Nedd4l

Top Publications

  1. Shi P, Cao X, Sweezer E, Kinney T, Williams N, Husted R, et al. Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2. Am J Physiol Renal Physiol. 2008;295:F462-70 pubmed publisher
    ..The absence of this gene is sufficient to produce salt-sensitive hypertension. This model provides an opportunity to further investigate mechanisms and consequences of this common disorder. ..
  2. Fouladkou F, Lu C, Jiang C, Zhou L, She Y, Walls J, et al. The ubiquitin ligase Nedd4-1 is required for heart development and is a suppressor of thrombospondin-1. J Biol Chem. 2010;285:6770-80 pubmed publisher
    ..These results suggest that Nedd4-1 is a suppressor of Tsp1 and that increased levels of Tsp-1 in the Nedd4-1 knock-out mice may have contributed to the developmental defect observed in the embryos. ..
  3. Boase N, Rychkov G, Townley S, Dinudom A, Candi E, Voss A, et al. Respiratory distress and perinatal lethality in Nedd4-2-deficient mice. Nat Commun. 2011;2:287 pubmed publisher
    ..Thus, we provide critical in vivo evidence that Nedd4-2 is essential for correct regulation of ENaC expression, fetal and postnatal lung function and animal survival. ..
  4. Gao S, Alarcon C, Sapkota G, Rahman S, Chen P, Goerner N, et al. Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling. Mol Cell. 2009;36:457-68 pubmed publisher
    ..Here, we identify Nedd4L as the ubiquitin ligase responsible for this step...
  5. Konstas A, Shearwin Whyatt L, Fotia A, Degger B, Riccardi D, Cook D, et al. Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein. J Biol Chem. 2002;277:29406-16 pubmed
    ..Because N4WBP5A is highly expressed in native renal collecting duct and other tissues that express ENaC, it is a likely candidate to modulate ENaC function in vivo. ..
  6. Fotia A, Dinudom A, Shearwin K, Koch J, Korbmacher C, Cook D, et al. The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels. FASEB J. 2003;17:70-2 pubmed
    ..These data suggest that Nedd4-2 WW3 and WW4 interact with distinct, noninterchangeable sites in ENaC and that to prevent Na+ feedback control of ENaC it is necessary to occlude both sites. ..
  7. Kamynina E, Debonneville C, Bens M, Vandewalle A, Staub O. A novel mouse Nedd4 protein suppresses the activity of the epithelial Na+ channel. FASEB J. 2001;15:204-214 pubmed
    ..Thus, these results suggest that the novel suppressor protein Nedd4-2 is the regulator of ENaC and hence a potential susceptibility gene for arterial hypertension. ..
  8. Harvey K, Dinudom A, Cook D, Kumar S. The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel. J Biol Chem. 2001;276:8597-601 pubmed
    ..We propose that KIAA0439 and Nedd4 proteins either play a redundant role in ENaC regulation or function in a tissue- and/or signal-specific manner to down-regulate ENaC. ..
  9. Conkright J, Apsley K, Martin E, Ridsdale R, Rice W, Na C, et al. Nedd4-2-mediated ubiquitination facilitates processing of surfactant protein-C. Am J Respir Cell Mol Biol. 2010;42:181-9 pubmed publisher
    ..Nedd4-2-mediated ubiquitination regulates lumenal relocation of SP-C, leading to processing and, ultimately, secretion of SP-C. ..

More Information


  1. Kimura T, Kawabe H, Jiang C, Zhang W, Xiang Y, Lu C, et al. Deletion of the ubiquitin ligase Nedd4L in lung epithelia causes cystic fibrosis-like disease. Proc Natl Acad Sci U S A. 2011;108:3216-21 pubmed publisher
    ..Here we show that knockout of the ubiquitin ligase Nedd4L (Nedd4-2) specifically in lung epithelia (surfactant protein C-expressing type II and Clara cells) causes cystic ..
  2. Ronzaud C, Loffing Cueni D, Hausel P, Debonneville A, Malsure S, Fowler Jaeger N, et al. Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension. J Clin Invest. 2013;123:657-65 pubmed publisher
    The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na+ channel (ENaC/SCNN1) to mediate Na+ homeostasis...
  3. Debonneville C, Flores S, Kamynina E, Plant P, Tauxe C, Thomas M, et al. Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression. EMBO J. 2001;20:7052-9 pubmed
    ..Moreover, they suggest a novel and complete signaling cascade for aldosterone-dependent regulation of ENaC. ..
  4. Roy A, Al Qusairi L, Donnelly B, Ronzaud C, Marciszyn A, Gong F, et al. Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action. J Clin Invest. 2015;125:3433-48 pubmed publisher
  5. Sanchez Perez A, Kumar S, Cook D. GRK2 interacts with and phosphorylates Nedd4 and Nedd4-2. Biochem Biophys Res Commun. 2007;359:611-5 pubmed
    ..Of possible significance is the phosphorylation of the threonine at position 466 in Nedd4, which is located in the area of the ww3 domain that binds ENaC. These results support and extend the role of GRK2 in sodium transport regulation. ..
  6. Ekberg J, Boase N, Rychkov G, Manning J, Poronnik P, Kumar S. Nedd4-2 (NEDD4L) controls intracellular Na(+)-mediated activity of voltage-gated sodium channels in primary cortical neurons. Biochem J. 2014;457:27-31 pubmed publisher
    ..The results of the present study provide the first physiological evidence for an essential function of Nedd4-2 in regulating Navs in the central nervous system...
  7. Jewett K, Zhu J, Tsai N. The tumor suppressor p53 guides GluA1 homeostasis through Nedd4-2 during chronic elevation of neuronal activity. J Neurochem. 2015;135:226-33 pubmed publisher
    ..Our findings demonstrate the first direct function of p53 in neuronal homeostasis and elucidate a new mechanism by which cortical neurons respond to chronic activity perturbation. ..
  8. Wang H, Sun R, Camera D, Zeng X, Jo E, Chan S, et al. Endoplasmic reticulum stress up-regulates Nedd4-2 to induce autophagy. FASEB J. 2016;30:2549-56 pubmed publisher
    ..Wang, H. Sun, R.-Q., Camera, D., Zeng, X.-Y., Jo, E., Chan, S. M. H., Herbert, T. P., Molero, J. C., Ye, J.-M. Endoplasmic reticulum stress up-regulates Nedd4-2 to induce autophagy. ..
  9. Yip K, Kolesnikoff N, Hauschild N, Biggs L, Lopez A, Galli S, et al. The Nedd4-2/Ndfip1 axis is a negative regulator of IgE-mediated mast cell activation. Nat Commun. 2016;7:13198 pubmed publisher
    ..Our findings reveal an important negative regulatory function for Nedd4-2 and Ndfip1 in IgE-dependent mast cell activity. ..
  10. Yu T, Calvo L, Anta B, L pez Benito S, L pez Bellido R, Vicente Garc a C, et al. In vivo regulation of NGF-mediated functions by Nedd4-2 ubiquitination of TrkA. J Neurosci. 2014;34:6098-106 pubmed publisher
    ..Our results indicate that the ubiquitination of the TrkA neurotrophin receptor plays a critical role in NGF-mediated functions, such as neuronal survival and sensitivity to pain...
  11. Goh C, Low L, Putz U, Gunnersen J, Hammond V, Howitt J, et al. Ndfip1 expression in developing neurons indicates a role for protein ubiquitination by Nedd4 E3 ligases during cortical development. Neurosci Lett. 2013;555:225-30 pubmed publisher
    ..This consistent but dynamic pattern of Ndfip1 expression in temporal and spatial domains of the cortical landscape is indicative of complex programs of protein ubiquitination during corticogenesis. ..
  12. Edinger R, Lebowitz J, Li H, Alzamora R, Wang H, Johnson J, et al. Functional regulation of the epithelial Na+ channel by IkappaB kinase-beta occurs via phosphorylation of the ubiquitin ligase Nedd4-2. J Biol Chem. 2009;284:150-7 pubmed publisher
    ..In summary, these results suggest a novel mode of ENaC regulation that occurs through IKKbeta-dependent Nedd4-2 phosphorylation at a recognized SGK1 and protein kinase A target site. ..
  13. Laedermann C, Cachemaille M, Kirschmann G, Pertin M, Gosselin R, Chang I, et al. Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain. J Clin Invest. 2013;123:3002-13 pubmed publisher
    ..Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L(-/-))...
  14. Jiang C, Kawabe H, Rotin D. The Ubiquitin Ligase Nedd4L Regulates the Na/K/2Cl Co-transporter NKCC1/SLC12A2 in the Colon. J Biol Chem. 2017;292:3137-3145 pubmed publisher
    The ubiquitin ligase Nedd4-like (Nedd4L, or Nedd4-2) binds to and regulates stability of the epithelial Na+ channel (ENaC) in salt-absorbing epithelia in the kidney, lung, and other tissues...
  15. Wu J, Liu X, Lai G, Yang X, Wang L, Zhao Y. Synergistical effect of 20-HETE and high salt on NKCC2 protein and blood pressure via ubiquitin-proteasome pathway. Hum Genet. 2013;132:179-87 pubmed publisher
    ..We propose that diverse levels of 20-HETE have diverse effects on blood pressure in different salt concentrations. ..
  16. Yanpallewar S, Wang T, Koh D, Quarta E, Fulgenzi G, Tessarollo L. Nedd4-2 haploinsufficiency causes hyperactivity and increased sensitivity to inflammatory stimuli. Sci Rep. 2016;6:32957 pubmed publisher
    Nedd4-2 (NEDD4L in humans) is a ubiquitin protein ligase best known for its role in regulating ion channel internalization and turnover...
  17. Chandran S, Li H, Dong W, Krasinska K, Adams C, Alexandrova L, et al. Neural precursor cell-expressed developmentally down-regulated protein 4-2 (Nedd4-2) regulation by 14-3-3 protein binding at canonical serum and glucocorticoid kinase 1 (SGK1) phosphorylation sites. J Biol Chem. 2011;286:37830-40 pubmed publisher
    ..We also propose that major site phosphorylation promotes cellular Nedd4-2 protein stability, which potentially represents a novel form of regulation for turnover of E3 ubiquitin ligases. ..
  18. Flores S, Loffing Cueni D, Kamynina E, Daidié D, Gerbex C, Chabanel S, et al. Aldosterone-induced serum and glucocorticoid-induced kinase 1 expression is accompanied by Nedd4-2 phosphorylation and increased Na+ transport in cortical collecting duct cells. J Am Soc Nephrol. 2005;16:2279-87 pubmed
    ..Hence, these data provide evidence in cortical collecting duct cells in vitro and in vivo that Sgk1-dependent phosphorylation of Nedd4-2 is part of the aldosterone response. ..
  19. Jewett K, Christian C, Bacos J, Lee K, Zhu J, Tsai N. Feedback modulation of neural network synchrony and seizure susceptibility by Mdm2-p53-Nedd4-2 signaling. Mol Brain. 2016;9:32 pubmed publisher
  20. Liang X, Butterworth M, Peters K, Walker W, Frizzell R. An obligatory heterodimer of 14-3-3beta and 14-3-3epsilon is required for aldosterone regulation of the epithelial sodium channel. J Biol Chem. 2008;283:27418-25 pubmed publisher
  21. Loffing Cueni D, Flores S, Sauter D, Daidié D, Siegrist N, Meneton P, et al. Dietary sodium intake regulates the ubiquitin-protein ligase nedd4-2 in the renal collecting system. J Am Soc Nephrol. 2006;17:1264-74 pubmed
    ..It is concluded that Nedd4-2 abundance is regulated by Na(+) diet, by a mechanism that likely involves aldosterone. This regulation may contribute to adaptation of apical ENaC activity to altered Na(+) intake...
  22. Lagnaz D, Arroyo J, Chavez Canales M, Vazquez N, Rizzo F, Spirlì A, et al. WNK3 abrogates the NEDD4-2-mediated inhibition of the renal Na+-Cl- cotransporter. Am J Physiol Renal Physiol. 2014;307:F275-86 pubmed publisher
    ..Together, these results suggest that a novel role for WNK3 on NCC expression at the plasma membrane, an effect apparently independent of the SPAK kinase and the aldosterone-SGK1 pathway. ..
  23. Minegishi S, Ishigami T, Kawamura H, Kino T, Chen L, Nakashima Sasaki R, et al. An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities. Int J Mol Sci. 2017;18: pubmed publisher
  24. Flasza M, Gorman P, Roylance R, Canfield A, Baron M. Alternative splicing determines the domain structure of WWP1, a Nedd4 family protein. Biochem Biophys Res Commun. 2002;290:431-7 pubmed
    ..We discuss the hypothesis that regulation of splice site usage may modulate the activity of WWP1 and possibly other Nedd4 family proteins. ..
  25. Kuratomi G, Komuro A, Goto K, Shinozaki M, Miyazawa K, Miyazono K, et al. NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor. Biochem J. 2005;386:461-70 pubmed
  26. Lee I, Dinudom A, Sanchez Perez A, Kumar S, Cook D. Akt mediates the effect of insulin on epithelial sodium channels by inhibiting Nedd4-2. J Biol Chem. 2007;282:29866-73 pubmed
    ..Together these data suggest that both Akt and Sgk are components of an insulin signaling pathway that increases Na(+) absorption by up-regulating membrane expression of ENaC via a regulatory system that involves inhibition of Nedd4-2. ..
  27. Anta B, Martín Rodríguez C, Gomis Pèrez C, Calvo L, López Benito S, Calderón García A, et al. Ubiquitin-specific Protease 36 (USP36) Controls Neuronal Precursor Cell-expressed Developmentally Down-regulated 4-2 (Nedd4-2) Actions over the Neurotrophin Receptor TrkA and Potassium Voltage-gated Channels 7.2/3 (Kv7.2/3). J Biol Chem. 2016;291:19132-45 pubmed publisher
    ..2/3 channel regulation. Our results demonstrate that USP36 binds to and regulates the actions of Nedd4-2 over different substrates affecting their expression and functions. ..
  28. Soundararajan R, Melters D, Shih I, Wang J, Pearce D. Epithelial sodium channel regulated by differential composition of a signaling complex. Proc Natl Acad Sci U S A. 2009;106:7804-9 pubmed publisher
  29. Hsia H, Kumar R, Lucà R, Takeda M, Courchet J, Nakashima J, et al. Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth. Proc Natl Acad Sci U S A. 2014;111:13205-10 pubmed publisher
    ..Our data demonstrate that Nedd4-family E3 ligases promote axonal growth and branching in the developing mammalian brain, where PTEN is not a relevant substrate. Instead, PTEN controls neurite growth by regulating Nedd4-1 expression. ..
  30. Fotia A, Ekberg J, Adams D, Cook D, Poronnik P, Kumar S. Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2. J Biol Chem. 2004;279:28930-5 pubmed
    ..Interestingly, Nedd4 suppressed the activity of Na(v)1.2 and Na(v)1.7 but was a poor inhibitor of Na(v)1.8. Our results provide evidence that Nedd4 and Nedd4-2 are likely to be key regulators of specific neuronal Na(v) channels in vivo. ..
  31. Zhao J, Wei J, Dong S, Bowser R, Zhang L, Jacko A, et al. Destabilization of Lysophosphatidic Acid Receptor 1 Reduces Cytokine Release and Protects Against Lung Injury. EBioMedicine. 2016;10:195-203 pubmed publisher
    ..Ubiquitin E3 ligase Nedd4L targets LPA1 for its site specific ubiquitination and degradation in the lysosome...
  32. Minegishi S, Ishigami T, Kino T, Chen L, Nakashima Sasaki R, Araki N, et al. An isoform of Nedd4-2 is critically involved in the renal adaptation to high salt intake in mice. Sci Rep. 2016;6:27137 pubmed publisher
    ..As we reported previously, both human and rodent Nedd4L/Nedd4-2 showed molecular diversity, with and without a C2 domain in their N-terminal...
  33. Goh C, Putz U, Howitt J, Low L, Gunnersen J, Bye N, et al. Nuclear trafficking of Pten after brain injury leads to neuron survival not death. Exp Neurol. 2014;252:37-46 pubmed publisher
    ..We conclude that nuclear trafficking of Pten following injury leads to neuron survival not death. ..
  34. Zhang Y, He X, Meng X, Wu X, Tong H, Zhang X, et al. Regulation of glutamate transporter trafficking by Nedd4-2 in a Parkinson's disease model. Cell Death Dis. 2017;8:e2574 pubmed publisher
    ..Furthermore, the SGK/PKC pathway is regulated downstream of Nedd4-2 in MPTP-treated mice. These findings indicate that Nedd4-2 may serve as a potential therapeutic target for the treatment of PD. ..
  35. Raikwar N, Vandewalle A, Thomas C. Nedd4-2 interacts with occludin to inhibit tight junction formation and enhance paracellular conductance in collecting duct epithelia. Am J Physiol Renal Physiol. 2010;299:F436-44 pubmed publisher
    ..In summary, we demonstrate that Nedd4-2 plays a role in tight junction assembly and the regulation of paracellular conductance in the collecting duct. ..
  36. Hatanaka T, Hatanaka Y, Setou M. Regulation of amino acid transporter ATA2 by ubiquitin ligase Nedd4-2. J Biol Chem. 2006;281:35922-30 pubmed
  37. Gille T, Randrianarison Pellan N, Goolaerts A, Dard N, Uzunhan Y, Ferrary E, et al. Hypoxia-induced inhibition of epithelial Na(+) channels in the lung. Role of Nedd4-2 and the ubiquitin-proteasome pathway. Am J Respir Cell Mol Biol. 2014;50:526-37 pubmed publisher
    ..Our data strongly suggest that Nedd4-2-mediated ubiquitination of ENaC leading to endocytosis and degradation of apical Na(+) channels is a key feature of hypoxia-induced inhibition of transepithelial alveolar Na(+) transport. ..
  38. Debonneville C, Staub O. Participation of the ubiquitin-conjugating enzyme UBE2E3 in Nedd4-2-dependent regulation of the epithelial Na+ channel. Mol Cell Biol. 2004;24:2397-409 pubmed
  39. Fotia A, Cook D, Kumar S. The ubiquitin-protein ligases Nedd4 and Nedd4-2 show similar ubiquitin-conjugating enzyme specificities. Int J Biochem Cell Biol. 2006;38:472-9 pubmed
    ..We also found that Ube2e3, an E2 previously shown to be used by Nedd4-2, is used less efficiently than UbcH5b. Our results suggest that for optimal ubiquitination Nedd4 and Nedd4-2 require the same E2 enzymes. ..
  40. Noyes N, Hampton B, Migliorini M, Strickland D. Regulation of Itch and Nedd4 E3 Ligase Activity and Degradation by LRAD3. Biochemistry. 2016;55:1204-13 pubmed publisher
    ..The identification of potential ligands for LRAD3 that may modulate LRAD3-induced activation of Itch and Nedd4 is likely to identify additional novel substrates and cellular functions for these important E3 ligases. ..
  41. Hammond V, Gunnersen J, Goh C, Low L, Hyakumura T, Tang M, et al. Ndfip1 is required for the development of pyramidal neuron dendrites and spines in the neocortex. Cereb Cortex. 2014;24:3289-300 pubmed publisher
    ..In addition, the PI3 kinase/Akt signaling pathway was altered. These results indicate that Ndfip1, through its Nedd4 effectors, is important for the development of dendrites and dendritic spines in the cortex. ..
  42. Fu J, Akhmedov D, Berdeaux R. The short isoform of the ubiquitin ligase NEDD4L is a CREB target gene in hepatocytes. PLoS ONE. 2013;8:e78522 pubmed publisher
    ..Here we show that fasting stimuli promote expression of the short isoform of the E3 ubiquitin ligase Nedd4l in primary mouse hepatocytes...
  43. Liang X, Peters K, Butterworth M, Frizzell R. 14-3-3 isoforms are induced by aldosterone and participate in its regulation of epithelial sodium channels. J Biol Chem. 2006;281:16323-32 pubmed
    ..Our studies show that aldosterone increases the expression of 14-3-3beta, which interacts with phospho-Nedd4-2 to block its interaction with ENaC, thus enhancing sodium absorption by increasing apical membrane ENaC density. ..
  44. Zhu J, Lee K, Jewett K, Man H, Chung H, Tsai N. Epilepsy-associated gene Nedd4-2 mediates neuronal activity and seizure susceptibility through AMPA receptors. PLoS Genet. 2017;13:e1006634 pubmed publisher
    ..Our findings provide critical information to the future development of therapeutic strategies for patients who carry mutations of Nedd4-2. ..
  45. Van Campenhout C, Eitelhuber A, Gloeckner C, Giallonardo P, Gegg M, Oller H, et al. Dlg3 trafficking and apical tight junction formation is regulated by nedd4 and nedd4-2 e3 ubiquitin ligases. Dev Cell. 2011;21:479-91 pubmed publisher
    ..Our findings reveal an unexpected evolutionary diversification of the vertebrate Dlg family in basolateral epithelium formation. ..
  46. Zhao G, Zhang P, Gong J, Zhang X, Wang P, Yin M, et al. Tmbim1 is a multivesicular body regulator that protects against non-alcoholic fatty liver disease in mice and monkeys by targeting the lysosomal degradation of Tlr4. Nat Med. 2017;23:742-752 pubmed publisher
    ..endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l was required for this process...
  47. Hallows K, Bhalla V, Oyster N, Wijngaarden M, Lee J, Li H, et al. Phosphopeptide screen uncovers novel phosphorylation sites of Nedd4-2 that potentiate its inhibition of the epithelial Na+ channel. J Biol Chem. 2010;285:21671-8 pubmed publisher
    ..These data identify phosphorylatable residues that activate Nedd4-2 and may work together with residues targeted by inhibitory kinases (e.g. SGK1 and protein kinase A) to govern Nedd4-2 regulation of epithelial ion transport. ..
  48. Arroyo J, Lagnaz D, Ronzaud C, Vazquez N, KO B, Moddes L, et al. Nedd4-2 modulates renal Na+-Cl- cotransporter via the aldosterone-SGK1-Nedd4-2 pathway. J Am Soc Nephrol. 2011;22:1707-19 pubmed publisher
    ..Taken together, these results suggest that aldosterone modulates NCC protein expression via a pathway involving SGK1 and Nedd4-2 and provides an explanation for the well-known aldosterone-induced increase in NCC protein expression. ..
  49. Umadevi N, Kumar S, Narayana N. Crystallization and preliminary X-ray diffraction studies of the WW4 domain of the Nedd4-2 ubiquitin-protein ligase. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005;61:1084-6 pubmed
    ..43, c = 103.21 A. Analysis of the self-rotation function suggests the presence of four WW4 molecules in the asymmetric unit, with a high unit-cell solvent content of 74%. ..