NEDD4L

Last updated
NEDD4L
Protein NEDD4L PDB 1wr3.png
Available structures
PDB Ortholog search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
Entrez

23327

83814

Ensembl

ENSG00000049759

ENSMUSG00000024589

UniProt

Q96PU5

Q8CFI0

RefSeq (mRNA)

NM_001114386
NM_031881

RefSeq (protein)
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

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.

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]

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

Related Research Articles

<span class="mw-page-title-main">Liddle's syndrome</span> Medical condition

Liddle's syndrome, also called Liddle syndrome, is a genetic disorder inherited in an autosomal dominant manner that is characterized by early, and frequently severe, high blood pressure associated with low plasma renin activity, metabolic alkalosis, low blood potassium, and normal to low levels of aldosterone. Liddle syndrome involves abnormal kidney function, with excess reabsorption of sodium and loss of potassium from the renal tubule, and is treated with a combination of low sodium diet and potassium-sparing diuretics. It is extremely rare, with fewer than 30 pedigrees or isolated cases having been reported worldwide as of 2008.

<span class="mw-page-title-main">ITCH</span> Protein-coding gene in the species Homo sapiens

ITCH is a HECT domain–containing E3 ubiquitin ligase that is ablated in non-agouti-lethal 18H mice. Itchy mice develop a severe immunological phenotype after birth that includes hyperplasia of lymphoid and hematopoietic cells, and stomach and lung inflammation. In humans ITCH deficiency causes altered physical growth, craniofacial morphology defects, defective muscle development, and aberrant immune system function. The ITCH gene is located on chromosome 20 in humans. ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated.

<span class="mw-page-title-main">NEDD4</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 is an enzyme that is, in humans, encoded by the NEDD4 gene.

<span class="mw-page-title-main">Sodium–hydrogen antiporter 3</span> Protein-coding gene in the species Homo sapiens

Sodium–hydrogen antiporter 3 also known as sodium–hydrogen exchanger 3 (NHE3) or solute carrier family 9 member 3 (SLC9A3) is a protein that in humans is encoded by the SLC9A3 gene.

<span class="mw-page-title-main">SCNN1B</span> Protein-coding gene in the species Homo sapiens

The SCNN1B gene encodes for the β subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1G, and SCNN1D.

<span class="mw-page-title-main">SCNN1A</span> Protein-coding gene in the species Homo sapiens

The SCNN1A gene encodes for the α subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1B, SCNN1G, and SCNN1D.

<span class="mw-page-title-main">SCNN1G</span> Protein-coding gene in the species Homo sapiens

The SCNN1G gene encodes for the γ subunit of the epithelial sodium channel ENaC in vertebrates. ENaC is assembled as a heterotrimer composed of three homologous subunits α, β, and γ or δ, β, and γ. The other ENAC subunits are encoded by SCNN1A, SCNN1B, and SCNN1D.

<span class="mw-page-title-main">WNK1</span> Protein-coding gene in the species Homo sapiens

WNK , also known as WNK1, is an enzyme that is encoded by the WNK1 gene. WNK1 is serine-threonine protein kinase and part of the "with no lysine/K" kinase WNK family. The predominant role of WNK1 is the regulation of cation-Cl− cotransporters (CCCs) such as the sodium chloride cotransporter (NCC), basolateral Na-K-Cl symporter (NKCC1), and potassium chloride cotransporter (KCC1) located within the kidney. CCCs mediate ion homeostasis and modulate blood pressure by transporting ions in and out of the cell. WNK1 mutations as a result have been implicated in blood pressure disorders/diseases; a prime example being familial hyperkalemic hypertension (FHHt).

<span class="mw-page-title-main">UBE2L3</span> Protein-coding gene in humans

Ubiquitin-conjugating enzyme E2 L3 (UBE2L3), also called UBCH7, is a protein that in humans is encoded by the UBE2L3 gene. As an E2 enzyme, UBE2L3 participates in ubiquitination to target proteins for degradation. The role of UBE2L3 in the ubiquitination of the NF-κB precursor implicated it in various major autoimmune diseases, including rheumatoid arthritis (RA), celiac disease, Crohn's disease (CD), and systemic lupus erythematosus.

<span class="mw-page-title-main">ASIC1</span> Protein-coding gene in humans

Acid-sensing ion channel 1 (ASIC1) also known as amiloride-sensitive cation channel 2, neuronal (ACCN2) or brain sodium channel 2 (BNaC2) is a protein that in humans is encoded by the ASIC1 gene. The ASIC1 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals. The cDNA of this gene was first cloned in 1996. The ASIC genes have splicing variants that encode different proteins that are called isoforms.

<span class="mw-page-title-main">SMURF1</span> Mammalian protein found in Homo sapiens

E3 ubiquitin-protein ligase SMURF1 is an enzyme that in humans is encoded by the SMURF1 gene. The SMURF1 Gene encodes a protein with a size of 757 amino acids and the molecular mass of this protein is 86114 Da.

<span class="mw-page-title-main">UBE2D2</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 D2 is a protein that in humans is encoded by the UBE2D2 gene.

<span class="mw-page-title-main">WWP1</span> Protein-coding gene in the species Homo sapiens

NEDD4-like E3 ubiquitin-protein ligase WWP1 is an enzyme that in humans is encoded by the WWP1 gene.

<span class="mw-page-title-main">UBE2L6</span> Protein-coding gene in the species Homo sapiens

Ubiquitin/ISG15-conjugating enzyme E2 L6 is a protein that in humans is encoded by the UBE2L6 gene.

<span class="mw-page-title-main">WWP2</span> Protein-coding gene in the species Homo sapiens

NEDD4-like E3 ubiquitin-protein ligase WWP2 also known as atrophin-1-interacting protein 2 (AIP2) or WW domain-containing protein 2 (WWP2) is an enzyme that in humans is encoded by the WWP2 gene.

<span class="mw-page-title-main">WNK4</span> Protein-coding gene in the species Homo sapiens

Serine/threonine protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene. Missense mutations cause a genetic form of pseudohypoaldosteronism type 2, also called Gordon syndrome.

<span class="mw-page-title-main">UBE2E1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 E1 is a protein that in humans is encoded by the UBE2E1 gene.

<span class="mw-page-title-main">Ankyrin-3</span> Protein-coding gene in the species Homo sapiens

Ankyrin-3 (ANK-3), also known as ankyrin-G, is a protein from ankyrin family that in humans is encoded by the ANK3 gene.

<span class="mw-page-title-main">HECW1</span> Protein-coding gene in the species Homo sapiens

HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1 is a protein that in humans is encoded by the HECW1 gene. In human it has 1606 amino acids and isoelectric point of 5.18.

<span class="mw-page-title-main">NDFIP1</span> Protein-coding gene in the species Homo sapiens

Nedd4 family interacting protein 1 is a protein that in humans is encoded by the NDFIP1 gene.

References

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  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000024589 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  6. 1 2 Harvey KF, Dinudom A, Cook DI, Kumar S (May 2001). "The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel". J. Biol. Chem. 276 (11): 8597–601. doi: 10.1074/jbc.C000906200 . PMID   11244092.
  7. ↑ Raikwar NS, Thomas CP (May 2008). "Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel". Am. J. Physiol. Renal Physiol. 294 (5): F1157-65. doi:10.1152/ajprenal.00339.2007. PMC   2424110 . PMID   18322022.
  8. ↑ "Entrez Gene: NEDD4L Neural precursor cell expressed, developmentally down-regulated 4-like".
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  17. 1 2 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.
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  20. ↑ Ekberg J, Schuetz F, Boase NA, Conroy SJ, Manning J, Kumar S, Poronnik P, Adams DJ (Apr 20, 2007). "Regulation of the voltage-gated K(+) channels KCNQ2/3 and KCNQ3/5 by ubiquitination. Novel role for Nedd4-2". J. Biol. Chem. 282 (16): 12135–42. doi: 10.1074/jbc.M609385200 . PMID   17322297.
  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.
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  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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  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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  32. 1 2 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.
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  36. ↑ Russo CJ, Melista E, Cui J, DeStefano AL, Bakris GL, Manolis AJ, Gavras H, Baldwin CT (Sep 2005). "Association of NEDD4L ubiquitin ligase with essential hypertension". Hypertension. 46 (3): 488–91. doi: 10.1161/01.HYP.0000178594.63193.c0 . PMID   16103266.
  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.

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