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.
Quick Facts Available structures, PDB ...
Close
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 (Navs), 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]
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]
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]
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]
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]
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]
NEDD4L has been shown to interact with SCNN1A.[6][41]
Harvey KF, Kumar S (May 1999). "Nedd4-like proteins: an emerging family of ubiquitin-protein ligases implicated in diverse cellular functions". Trends Cell Biol. 9 (5): 166–9. doi:10.1016/s0962-8924(99)01541-x. PMID 10322449.
Araki N, Umemura M, Miyagi Y, Yabana M, Miki Y, Tamura K, Uchino K, Aoki R, Goshima Y, Umemura S, Ishigami T (Mar 2008). "Expression, transcription, and possible antagonistic interaction of the human Nedd4L gene variant: implications for essential hypertension". Hypertension. 51 (3): 773–7. doi:10.1161/HYPERTENSIONAHA.107.102061. PMID 18268134.
Itani OA, Campbell JR, Herrero J, Snyder PM, Thomas CP (Nov 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.
Ronzaud C, Loffing-Cueni D, Hausel P, Debonneville A, Malsure SR, Fowler-Jaeger N, Boase NA, Perrier R, Maillard M, Yang B, Stokes JB, Koesters R, Kumar S, Hummler E, Loffing J, Staub O (Feb 1, 2013). "Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension". J. Clin. Invest. 123 (2): 657–65. doi:10.1172/JCI61110. PMC 3561795. PMID 23348737.
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.
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.
Nagaki K, Yamamura H, Shimada S, Saito T, Hisanaga S, Taoka M, Isobe T, Ichimura T (May 30, 2006). "14-3-3 Mediates phosphorylation-dependent inhibition of the interaction between the ubiquitin E3 ligase Nedd4-2 and epithelial Na+ channels". Biochemistry. 45 (21): 6733–40. doi:10.1021/bi052640q. PMID 16716084.
Bruce MC, Kanelis V, Fouladkou F, Debonneville A, Staub O, Rotin D (Oct 1, 2008). "Regulation of Nedd4-2 self-ubiquitination and stability by a PY motif located within its HECT-domain". Biochem. J. 415 (1): 155–63. doi:10.1042/BJ20071708. PMID 18498246.
Oberfeld B, Ruffieux-Daidié D, Vitagliano JJ, Pos KM, Verrey F, Staub O (Jul 2011). "Ubiquitin-specific protease 2-45 (Usp2-45) binds to epithelial Na+ channel (ENaC)-ubiquitylating enzyme Nedd4-2". Am. J. Physiol. Renal Physiol. 301 (1): F189-96. doi:10.1152/ajprenal.00487.2010. PMID 21478478.
Boase NA, Rychkov GY, Townley SL, Dinudom A, Candi E, Voss AK, Tsoutsman T, Semsarian C, Melino G, Koentgen F, Cook DI, Kumar S (2011). "Respiratory distress and perinatal lethality in Nedd4-2-deficient mice". Nat Commun. 2 (4): 287. Bibcode:2011NatCo...2..287B. doi:10.1038/ncomms1284. PMC 3104547. PMID 21505443.
Kimura T, Kawabe H, Jiang C, Zhang W, Xiang YY, Lu C, Salter MW, Brose N, Lu WY, Rotin D (Feb 22, 2011). "Deletion of the ubiquitin ligase Nedd4L in lung epithelia causes cystic fibrosis-like disease". Proc. Natl. Acad. Sci. U.S.A. 108 (8): 3216–21. Bibcode:2011PNAS..108.3216K. doi:10.1073/pnas.1010334108. PMC 3044364. PMID 21300902.
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.
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.
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.
- 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.