NEDD4L

Neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L) or NEDD4-2 is an enzyme (ubiquitin ligase) of the NEDD4 family. In human the protein is encoded by the NEDD4L gene.^[5][6][7][8] In mouse the protein is commonly known as NEDD4-2 and the gene Nedd4-2.

NEDD4L
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2LAJ, 2LB2, 2LTY, 2MPT, 2NSQ, 2ONI, 3JVZ, 3JW0, 5HPK
Identifiers
Aliases	NEDD4L, NEDD4-2, NEDD4.2, RSP5, hNEDD4-2, neural precursor cell expressed, developmentally down-regulated 4-like, E3 ubiquitin protein ligase, PVNH7, NEDD4 like E3 ubiquitin protein ligase
External IDs	OMIM: 606384 MGI: 1933754 HomoloGene: 86986 GeneCards: NEDD4L
Gene location (Human) Chr. Chromosome 18 (human)^[1] Band 18q21.31 Start 58,044,226 bp^[1] End 58,401,540 bp^[1]
Gene location (Mouse) Chr. Chromosome 18 (mouse)^[2] Band 18|18 E1 Start 64,887,705 bp^[2] End 65,217,828 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in ganglionic eminence right lung secondary oocyte body of pancreas upper lobe of left lung rectum kidney prostate body of stomach middle temporal gyrus Top expressed in olfactory tubercle mammillary body nucleus accumbens secondary oocyte habenula left lung lobe ventromedial nucleus cerebellar vermis subiculum ganglionic eminence More reference expression data BioGPS n/a
Gene ontology Molecular function potassium channel inhibitor activity sodium channel regulator activity transmembrane transporter binding sodium channel inhibitor activity potassium channel regulator activity protein binding transferase activity ubiquitin-protein transferase activity ubiquitin protein ligase activity Cellular component cytosol plasma membrane intracellular anatomical structure nucleoplasm extracellular exosome endosome multivesicular body Golgi apparatus cytoplasm Biological process negative regulation of sodium ion transmembrane transport cell differentiation positive regulation of caveolin-mediated endocytosis excretion positive regulation of protein catabolic process viral life cycle sodium ion transport cellular sodium ion homeostasis negative regulation of sodium ion transmembrane transporter activity regulation of membrane potential regulation of ion transmembrane transport ventricular cardiac muscle cell action potential response to metal ion negative regulation of transcription by RNA polymerase II protein monoubiquitination water homeostasis regulation of membrane depolarization protein K48-linked ubiquitination positive regulation of endocytosis negative regulation of protein localization to cell surface ion transmembrane transport negative regulation of potassium ion transmembrane transporter activity protein ubiquitination regulation of potassium ion transmembrane transporter activity regulation of protein catabolic process negative regulation of potassium ion transmembrane transport regulation of membrane repolarization positive regulation of dendrite extension proteasome-mediated ubiquitin-dependent protein catabolic process protein polyubiquitination viral process ubiquitin-dependent protein catabolic process regulation of protein stability regulation of dendrite morphogenesis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23327 83814 Ensembl ENSG00000049759 ENSMUSG00000024589 UniProt Q96PU5 Q8CFI0 RefSeq (mRNA) NM_001144964 NM_001144965 NM_001144966 NM_001144967 NM_001144968 NM_001144969 NM_001144970 NM_001144971 NM_001243960 NM_015277 NM_001114386 NM_031881 RefSeq (protein) NP_001138436 NP_001138437 NP_001138438 NP_001138439 NP_001138440 NP_001138441 NP_001138442 NP_001138443 NP_001230889 NP_056092 NP_001107858 NP_114087 NP_001390936 NP_001390937 NP_001390938 NP_001390942 Location (UCSC) Chr 18: 58.04 – 58.4 Mb Chr 18: 64.89 – 65.22 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

NEDD4-2 has been shown to ubiquitinate and therefore down regulate the epithelial sodium channel (ENaC) in the collecting ducts of the kidneys, therefore opposing the actions of aldosterone and increasing salt excretion. In Liddle's Syndrome NEDD4 is unable to bind to the ENaC and lead to salt retention and hypertension occur.^[9]

NEDD4L belongs to the NEDD4 family of E3 HECT domain ubiquitin ligases.^{[10][11][12][13]} It is the closest homologue of NEDD4, the prototypic member of the family and probably arose as a result of gene duplication.^[12] While NEDD4 orthologues are present in all eukaryotes, NEDD4L proteins are limited to vertebrates. NEDD4L proteins are known to be involved in regulating many membrane proteins via ubiquitination and endocytosis.^[10]

NEDD4L protein is expressed widely. The primary targets of NEDD4-2 include the epithelial sodium channel (ENaC), the Na+-Cl- co-transporter (NCC), and the voltage gated sodium channels (Na_vs), although additional targets are predicted from in vitro studies. NEDD4-2 gene in mice is essential for animal survival and the polymorphisms in NEDD4L are associated with human hypertension.^[11][13]

Protein architecture

The NEDD4-2 protein consists of an amino-terminal Ca2+-phospholipid binding domain (C2), 4 WW domains (protein-protein interaction domains) and the carboxyl-terminal HECT domain (ubiquitin ligase domain). The WW domains in the protein are responsible for binding the substrates, regulatory proteins and adaptors. These domains generally recognize PPxY (or similar) motifs in the target proteins.^{[10][11][12][13]}

Expression

Human NEDD4L gene is located on chromosome 18q12.31 with 38 exons that transcribe multiple splice variants of NEDD4L.^[14][15] The protein expressed in the brain, lung, heart and the kidney contains a C2 domain. Three predominant forms of NEDD4L are isoform I containing a novel C2 domain with a start codon in exon1, isoform II with an intact conserved C2 domain consisting of an alternate start codon in exon 1 upstream of the actual start codon of the isoform 1, and isoform III lacking a C2 domain due to exon 2a–3 splicing. Isoform 1 is found to be abundant in kidney and adrenal gland whereas isoform 2 is predominantly found in the lungs.^[15][16] The antibodies specific to NEDD4-2 recognize two species of ~110-115 kDa in most tissues, with one being variable depending on the tissue.^[15][17]

Function

NEDD4L is a ubiquitin-protein ligase (E3) that accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then transfers it to specific substrates.^[11][12][13]

In vivo NEDD4-2 regulates ENaC in the lung and kidney, the renal NCC and several Navs.^{[16][18][19][20]} It has also been shown to regulate EGFR, TGFβ receptor and WNT signalling.^[21][22] NEDD4L has been implicated in viral budding and viral latency processes via ubiquitination of viral proteins.^[11][13][23] In vitro data implicate NEDD4-2 in the regulation of many other proteins, including several ion channels and transporters. However most of these results have not been validated in vivo.^[12][13]

Regulation of NEDD4-2

NDFIP1 and NDFIP2 proteins bind NEDD4-2 and regulate its activity and/or interaction with substrates.^[24][25] NEDD4-2 phosphorylation by kinases SGK1 and AKT in response to insulin and aldosterone signaling results in its interaction with 14-3-3 proteins. 14-3-3 binding to NEDD4-2 inhibits its ability to bind and ubiquitinate its substrates (such the ENaC subunits).^{[26][27][28][29]} Autoubiquitination and deubiquitylation of NEDD4-2 by USP2-45 are also known to maintain NEDD4-2 protein stability.^[30][31]

Clinical significance

NEDD4L is a critical regulator of renal ENaC and NCC and malfunction of this pathway has been linked to hypertension, as in Liddle's syndrome, a genetic disorder where mutations in the ENaC subunits abrogate NEDD4L binding.^[17][32][33] In mouse, NEDD4-2 deletion leads to increased cell surface expression and activity of ENaC in the lung, resulting in premature clearance of lung fluid, airway drying, lung inflammation and perinatal lethality.^[32][34]

Specific deletion of NEDD4-2 in mouse renal tubules leads to increased expression of ENaC and NCC. Consistent with the critical function in ENaC and NCC regulation, NEDDL polymorphisms are linked to essential hypertension in certain human populations.^[35][36] Specific deletion of NEDD4-2 in mouse neurons results in axonal branching defects.^[37] Isolated fetal cortical neurons from NEDD4-2 knockout mice show defective regulation of voltage-gated sodium currents,^[38] and in animal models of neuropathic pain NEDD4-2 expression has been found to be downregulated.^[39] Also NEDD4-2-deficiency results in hyperexcitability of DRG neurons and contributes to pathological pain^[40]

Interactions

NEDD4L has been shown to interact with SCNN1A.^[6][41]

Notes

References

1. GRCh38: Ensembl release 89: ENSG00000049759 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024589 - Ensembl, May 2017
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21. Gao S, Alarcón C, Sapkota G, Rahman S, Chen PY, Goerner N, Macias MJ, Erdjument-Bromage H, Tempst P, Massagué J (Nov 13, 2009). "Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling". Mol. Cell. 36 (3): 457–68. doi:10.1016/j.molcel.2009.09.043. PMC 2796330. PMID 19917253.
22. Zhang Y, Ding Y, Chen YG, Tao Q (Aug 1, 2014). "NEDD4L regulates convergent extension movements in Xenopus embryos via Disheveled-mediated non-canonical Wnt signaling". Dev. Biol. 392 (1): 15–25. doi:10.1016/j.ydbio.2014.05.003. PMID 24833518.
23. Chung HY, Morita E, von Schwedler U, Müller B, Kräusslich HG, Sundquist WI (May 2008). "NEDD4L overexpression rescues the release and infectivity of human immunodeficiency virus type 1 constructs lacking PTAP and YPXL late domains". J. Virol. 82 (10): 4884–97. doi:10.1128/JVI.02667-07. PMC 2346761. PMID 18321968.
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25. Shearwin-Whyatt L, Dalton HE, Foot N, Kumar S (Jun 2006). "Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins". BioEssays. 28 (6): 617–28. doi:10.1002/bies.20422. PMID 16700065.
26. Snyder PM, Olson DR, Kabra R, Zhou R, Steines JC (Oct 29, 2004). "cAMP and serum and glucocorticoid-inducible kinase (SGK) regulate the epithelial Na(+) channel through convergent phosphorylation of Nedd4-2". J. Biol. Chem. 279 (44): 45753–8. doi:10.1074/jbc.M407858200. PMID 15328345.
27. Bhalla V, Daidié D, Li H, Pao AC, LaGrange LP, Wang J, Vandewalle A, Stockand JD, Staub O, Pearce D (Dec 2005). "Serum- and glucocorticoid-regulated kinase 1 regulates ubiquitin ligase neural precursor cell-expressed, developmentally down-regulated protein 4-2 by inducing interaction with 14-3-3". Mol. Endocrinol. 19 (12): 3073–84. doi:10.1210/me.2005-0193. PMID 16099816. S2CID 11498723.
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37. Hsia HE, Kumar R, Luca R, Takeda M, Courchet J, Nakashima J, Wu S, Goebbels S, An W, Eickholt BJ, Polleux F, Rotin D, Wu H, Rossner MJ, Bagni C, Rhee JS, Brose N, Kawabe H (Sep 9, 2014). "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. 111 (36): 13205–10. Bibcode:2014PNAS..11113205H. doi:10.1073/pnas.1400737111. PMC 4246980. PMID 25157163.
38. Ekberg JA, Boase NA, Rychkov G, Manning J, Poronnik P, Kumar S (Jan 1, 2014). "Nedd4-2 (NEDD4L) controls intracellular Na(+)-mediated activity of voltage-gated sodium channels in primary cortical neurons". Biochem. J. 457 (1): 27–31. doi:10.1042/BJ20131275. PMID 24152020.^{[permanent dead link]}
39. Laedermann CJ, Cachemaille M, Kirschmann G, Pertin M, Gosselin RD, Chang I, Albesa M, Towne C, Schneider BL, Kellenberger S, Abriel H, Decosterd I (Jul 1, 2013). "Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain". J. Clin. Invest. 123 (7): 3002–13. doi:10.1172/JCI68996. PMC 3696561. PMID 23778145.
40. Cachemaille M, Laedermann CJ, Pertin M, Abriel H, Gosselin RD, Decosterd I (Dec 27, 2012). "Neuronal expression of the ubiquitin ligase Nedd4-2 in rat dorsal root ganglia: modulation in the spared nerve injury model of neuropathic pain". Neuroscience. 227: 370–80. doi:10.1016/j.neuroscience.2012.09.044. PMID 23022218. S2CID 26108834.
41. Malbert-Colas L, Nicolas G, Galand C, Lecomte MC, Dhermy D (Jul 2003). "Identification of new partners of the epithelial sodium channel alpha subunit". Comptes Rendus Biologies. 326 (7): 615–24. doi:10.1016/s1631-0691(03)00154-9. PMID 14556380.

Further reading

• Cook DI, Dinudom A, Komwatana P, Kumar S, Young JA (2002). "Patch-clamp studies on epithelial sodium channels in salivary duct cells". Cell Biochem. Biophys. 36 (2–3): 105–13. doi:10.1385/CBB:36:2-3:105. PMID 12139396. S2CID 32064659.
• Nuber U, Schwarz S, Kaiser P, Schneider R, Scheffner M (1996). "Cloning of human ubiquitin-conjugating enzymes UbcH6 and UbcH7 (E2-F1) and characterization of their interaction with E6-AP and RSP5". J. Biol. Chem. 271 (5): 2795–800. doi:10.1074/jbc.271.5.2795. PMID 8576257.
• Ishikawa K, Nagase T, Nakajima D, Seki N, Ohira M, Miyajima N, Tanaka A, Kotani H, Nomura N, Ohara O (1997). "Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro". DNA Res. 4 (5): 307–13. doi:10.1093/dnares/4.5.307. PMID 9455477.
• Winberg G, Matskova L, Chen F, Plant P, Rotin D, Gish G, Ingham R, Ernberg I, Pawson T (2000). "Latent membrane protein 2A of Epstein-Barr virus binds WW domain E3 protein-ubiquitin ligases that ubiquitinate B-cell tyrosine kinases". Mol. Cell. Biol. 20 (22): 8526–35. doi:10.1128/MCB.20.22.8526-8535.2000. PMC 102158. PMID 11046148.
• Kikonyogo A, Bouamr F, Vana ML, Xiang Y, Aiyar A, Carter C, Leis J (2001). "Proteins related to the Nedd4 family of ubiquitin protein ligases interact with the L domain of Rous sarcoma virus and are required for gag budding from cells". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11199–204. Bibcode:2001PNAS...9811199K. doi:10.1073/pnas.201268998. PMC 58707. PMID 11562473.
• Snyder PM, Olson DR, Thomas BC (2002). "Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel". J. Biol. Chem. 277 (1): 5–8. doi:10.1074/jbc.C100623200. PMID 11696533.
• Debonneville C, Flores SY, Kamynina E, Plant PJ, Tauxe C, Thomas MA, Münster C, Chraïbi A, Pratt JH, Horisberger JD, Pearce D, Loffing J, Staub O (2001). "Phosphorylation of Nedd4-2 by Sgk1 regulates epithelial Na(+) channel cell surface expression". EMBO J. 20 (24): 7052–9. doi:10.1093/emboj/20.24.7052. PMC 125341. PMID 11742982.
• Harvey KF, Shearwin-Whyatt LM, Fotia A, Parton RG, Kumar S (2002). "N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein". J. Biol. Chem. 277 (11): 9307–17. doi:10.1074/jbc.M110443200. PMID 11748237.
• Chen H, Ross CA, Wang N, Huo Y, MacKinnon DF, Potash JB, Simpson SG, McMahon FJ, DePaulo Jr JR, McInnis MG (2001). "NEDD4L on human chromosome 18q21 has multiple forms of transcripts and is a homologue of the mouse Nedd4-2 gene". Eur. J. Hum. Genet. 9 (12): 922–30. doi:10.1038/sj.ejhg.5200747. PMID 11840194.
• Konstas AA, Shearwin-Whyatt LM, Fotia AB, Degger B, Riccardi D, Cook DI, Korbmacher C, Kumar S (2002). "Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein". J. Biol. Chem. 277 (33): 29406–16. doi:10.1074/jbc.M203018200. PMID 12050153.
• Dunn DM, Ishigami T, Pankow J, von Niederhausern A, Alder J, Hunt SC, Leppert MF, Lalouel JM, Weiss RB (2002). "Common variant of human NEDD4L activates a cryptic splice site to form a frameshifted transcript". J. Hum. Genet. 47 (12): 665–76. doi:10.1007/s100380200102. PMID 12522688.
• Asher C, Sinha I, Garty H (2003). "Characterization of the interactions between Nedd4-2, ENaC, and sgk-1 using surface plasmon resonance". Biochim. Biophys. Acta. 1612 (1): 59–64. doi:10.1016/S0005-2736(03)00083-X. PMID 12729930.
• Itani OA, Campbell JR, Herrero J, Snyder PM, Thomas CP (2003). "Alternate promoters and variable splicing lead to hNedd4-2 isoforms with a C2 domain and varying number of WW domains". Am. J. Physiol. Renal Physiol. 285 (5): F916-29. doi:10.1152/ajprenal.00203.2003. PMID 12876068. S2CID 1429872.
• Boehmer C, Henke G, Schniepp R, Palmada M, Rothstein JD, Bröer S, Lang F (2003). "Regulation of the glutamate transporter EAAT1 by the ubiquitin ligase Nedd4-2 and the serum and glucocorticoid-inducible kinase isoforms SGK1/3 and protein kinase B". J. Neurochem. 86 (5): 1181–8. doi:10.1046/j.1471-4159.2003.01937.x. PMID 12911626. S2CID 20290123.
• Malbert-Colas L, Nicolas G, Galand C, Lecomte MC, Dhermy D (2003). "Identification of new partners of the epithelial sodium channel alpha subunit". Comptes Rendus Biologies. 326 (7): 615–24. doi:10.1016/s1631-0691(03)00154-9. PMID 14556380.
• Qi H, Grenier J, Fournier A, Labrie C (2003). "Androgens differentially regulate the expression of NEDD4L transcripts in LNCaP human prostate cancer cells". Mol. Cell. Endocrinol. 210 (1–2): 51–62. doi:10.1016/j.mce.2003.08.009. PMID 14615060. S2CID 33109822.