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Biology:NEDD4

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 (whence "NEDD4") is an enzyme that is, in humans, encoded by the NEDD4 gene.[1][2]

NEDD4 is an E3 ubiquitin ligase enzyme, that targets proteins for ubiquitination.[3] NEDD4 is, in eukaryotes, a highly conserved gene, and the founding member of the NEDD4 family of E3 HECT ubiquitin ligases, which in humans consists of 9 members: [4] [5] [6]

  • NEDD4 (the core topic of this article)
  • NEDD4-2 (or NEDD4L)
  • ITCH
  • SMURF1
  • SMURF2
  • WWP1
  • WWP2
  • NEDL1 (HECW1)
  • NEDDL2 (HECW2)].

NEDD4 regulates a large number of membrane proteins, such as ion channels and membrane receptors, via ubiquitination and endocytosis; its eponymous protein is widely expressed, and a large number of proteins have been predicted or demonstrated to bind in vitro.

In vivo, it is involved in the regulation of a diverse range of processes,[3] including

  • insulin-like growth factor signalling,
  • neuronal architecture, and
  • viral budding.

NEDD4 also is an essential protein in animals, both for development and for survival. [7]

Structure

The NEDD4 protein has a modular structure that is shared among the NEDD4 family, consisting of an amino-terminal C2 calcium-dependent phospholipid binding domain, 3-4 WW protein-protein interaction domains, and a carboxyl-terminal catalytic HECT ubiquitin ligase domain.[8] The C2 domain targets proteins to the phospholipid membrane, and can also be involved in targeting substrates.[9] The WW domains interact with proline rich PPxY motifs in target proteins to mediate interactions with substrates and adaptors.[10] The catalytic HECT domain forms a thioester bond with activated ubiquitin transferred from an E2 ubiquitin conjugating enzyme, before transferring ubiquitin directly to a specific substrate.[4]

Expression

The human NEDD4 gene is located on chromosome 15q21.3, and consists of 30 exons that transcribe five protein variants of NEDD4, all of which vary in the C2 domain but share 100% identity from the first WW domain through to the end of the protein.[11] The mouse Nedd4 gene is located on chromosome 9.[1] NEDD4 is a 120kDa protein that is expressed in most tissues, including brain, heart, lung, kidney, and skeletal muscle.[12] The NEDD4 protein localizes to the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery.[1][12]

Function

In vitro, NEDD4 has been shown to bind and ubiquitinate a number of ion channels and membrane transporters resulting in their subsequent endocytosis and degradation by the proteasome, including the epithelial sodium channel (ENaC), voltage-gated calcium and voltage-gated sodium channels.[13][14][15][16]

NEDD4 mediates ubiquitination and subsequent down-regulation of components of the epidermal growth factor (EGF) signalling pathway, such as HER3 and HER4 EGF receptors, and ACK.[17][18][19]

The fibroblast growth factor receptor 1 (FGFR1) undergoes NEDD4 mediated ubiquitination and down-regulation, and contains a novel site (VL***PSR) that binds the C2 and WW3 domain of NEDD4.[20]

There is a role for NEDD4 in viral budding via ubiquitination of viral matrix proteins for a number of viruses,[6] and NEDD4 also interacts with components of the endocytic machinery required for budding.[21]

NEDD4 can also function independently of its ubiquitin ligase activity. NEDD4 interacts with VEGFR2, leading to the degradation of VEGFR2 irrespective of whether the HECT domain is catalytically active.[22]

NEDD4 can bind and ubiquitinate the epithelial sodium channel (ENaC), leading to down-regulation of sodium channel activity.[14] However, in vivo studies have implicated the NEDD4 family member NEDD4-2 as the main ligase responsible for ENaC regulation.[23][24][25]

Regulation

NEDD4 activity can be regulated by auto-inhibition, whereby the C2 domain binds to the HECT domain to create an inhibitory conformation of the protein.[26] This auto-inhibitory conformation can be disrupted by the presence of calcium, by proteins that bind to NEDD4 to prevent this conformation, or by phosphorylation of NEDD4 at specific tyrosine residues to activate NEDD4 ubiquitin ligase activity.[26][27]

The NDFIP1 and NDFIP2 proteins function as adaptor proteins that can facilitate NEDD4 binding to substrates that lack PY motifs, as well as a role in binding NEDD4 to abrogate auto-inhibition.[28][29] NDFIP1 may also regulate NEDD4 recruitment to exosomes for secretion.[30]

Oxidative stress induces the activation of NEDD4 transcription via the FOXM1B transcription factor.[31] Ras signalling also up-regulates NEDD4 transcription.[32]

Physiological significance

In vivo, NEDD4 is involved in the regulation of insulin and insulin-like growth factor (IGF-1) signalling by regulating the amount of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) on the cell surface.[7][33]

The deletion of NEDD4 in mice leads to a reduced number of effector T-cells, and a slower T-cell response to antigen, suggesting that NEDD4 may function to convert naïve T-cells into activated T-cells.[34]

NEDD4 plays an important role in neuronal development, and is responsible for the formation and arborisation of dendrites in neurons by forming a signalling complex with TINK and Rap2A.[35] It is also required for proper formation and function of neuromuscular junctions, and normal numbers of cranial neural crest cells, motor neurons and axons.[36][37]

NEDD4 has been shown to interact with and ubiquitinate the tumour suppressor protein PTEN in vitro, resulting in PTEN proteasomal degradation or trafficking.[38][39] The in vivo role of NEDD4 in PTEN regulation is less clear. There is some evidence from NEDD4 deficient mice that NEDD4 does not target PTEN for degradation or trafficking.[7][40][41] However, in other in vivo models, and in many human cancer cell lines, NEDD4 does appear responsible for the degradation of PTEN.[32][42][43][44][45] NEDD4 regulation of PTEN may only occur in specific biological contexts.

The role of NEDD4 in negatively regulating tumour suppressor proteins is consistent with the frequent overexpression of NEDD4 in many different types of human cancers.[46][47] Decreased levels of NEDD4 have also been associated with some cancers, including neuroblastoma and pancreatic cancer where the NEDD4 directly targets the respective oncoproteins N-Myc and c-Myc associated with these cancers for degradation.[48]

Viral budding

NEDD4 may be hijacked by viral proteins (for example, by UL56 from Herpes simplex virus 2, or by protein VP40 from Ebola virus.[49] Such infection aids viruses in taking over the ESCRT pathway which is essential for successful budding of the virions from the plasma membrane. [vague] The hijacking mechanisms operate by exploiting evolution, the chemical evolution of (viral) genes coding for traits that exploit a short linear motif mimicry. In the case of NEDD4, viral proteins mimic the PPxY recognition motif of WW domains that are part of NEDD4.[49]

Notes


References

  1. ↑ 1.0 1.1 1.2 "cDNA cloning, expression analysis, and mapping of the mouse Nedd4 gene". Genomics 40 (3): 435–43. May 1997. doi:10.1006/geno.1996.4582. PMID 9073511. 
  2. ↑ "Yeast RSP5 and its human homolog hRPF1 potentiate hormone-dependent activation of transcription by human progesterone and glucocorticoid receptors". Mol Cell Biol 16 (6): 2594–605. Jul 1996. doi:10.1128/MCB.16.6.2594. PMID 8649367. 
  3. ↑ 3.0 3.1 "NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor". The EMBO Journal 39 (3): e102771. February 2020. doi:10.15252/embj.2019102771. PMID 31867777. 
  4. ↑ 4.0 4.1 "Physiological functions of the HECT family of ubiquitin ligases". Nat. Rev. Mol. Cell Biol. 10 (6): 398–409. 2009. doi:10.1038/nrm2690. PMID 19436320. 
  5. ↑ "Mammalian HECT ubiquitin-protein ligases: biological and pathophysiological aspects". Biochim. Biophys. Acta 1843 (1): 61–74. 2014. doi:10.1016/j.bbamcr.2013.03.024. PMID 23545411. 
  6. ↑ 6.0 6.1 "Nedd4 and Nedd4-2: closely related ubiquitin-protein ligases with distinct physiological functions". Cell Death Differ. 17 (1): 68–77. 2010. doi:10.1038/cdd.2009.84. PMID 19557014. 
  7. ↑ 7.0 7.1 7.2 "Nedd4 controls animal growth by regulating IGF-1 signaling". Sci Signal 1 (38): ra5. 2008. doi:10.1126/scisignal.1160940. PMID 18812566. 
  8. ↑ "Nedd4-like proteins: an emerging family of ubiquitin-protein ligases implicated in diverse cellular functions". Trends Cell Biol. 9 (5): 166–9. 1999. doi:10.1016/s0962-8924(99)01541-x. PMID 10322449. 
  9. ↑ "The C2 domain of the Rsp5 ubiquitin ligase binds membrane phosphoinositides and directs ubiquitination of endosomal cargo". J. Cell Biol. 165 (1): 135–44. 2004. doi:10.1083/jcb.200309026. PMID 15078904. 
  10. ↑ "Characterization of a novel protein-binding module--the WW domain". FEBS Lett. 369 (1): 67–71. 1995. doi:10.1016/0014-5793(95)00550-s. PMID 7641887. 
  11. ↑ "NEDD4 neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase [Homo sapiens (human)"]. NCBI. https://www.ncbi.nlm.nih.gov/gene/4734. 
  12. ↑ 12.0 12.1 "Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes". Genes Cells 3 (11): 751–63. 1998. doi:10.1046/j.1365-2443.1998.00227.x. PMID 9990509. 
  13. ↑ "WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome". EMBO J. 15 (10): 2371–80. 1996. doi:10.1002/j.1460-2075.1996.tb00593.x. PMID 8665844. 
  14. ↑ 14.0 14.1 "Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+". Proc. Natl. Acad. Sci. U.S.A. 95 (12): 7169–73. 1998. doi:10.1073/pnas.95.12.7169. PMID 9618557. Bibcode: 1998PNAS...95.7169D. 
  15. ↑ "Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) controls the sorting of newly synthesized Ca(V)1.2 calcium channels". J. Biol. Chem. 286 (11): 8829–38. 2011. doi:10.1074/jbc.M110.166520. PMID 21220429. 
  16. ↑ "Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2". J. Biol. Chem. 279 (28): 28930–5. 2004. doi:10.1074/jbc.M402820200. PMID 15123669. http://espace.library.uq.edu.au/view/UQ:74618/UQ74618_OA.pdf. 
  17. ↑ "Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells". FASEB J. 23 (6): 1935–45. 2009. doi:10.1096/fj.08-121947. PMID 19193720. 
  18. ↑ "The E3 ubiquitin ligase NEDD4 negatively regulates HER3/ErbB3 level and signaling". Oncogene 34 (9): 1105–15. 2014. doi:10.1038/onc.2014.56. PMID 24662824. 
  19. ↑ "HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK". Mol. Cell. Biol. 30 (6): 1541–54. 2010. doi:10.1128/MCB.00013-10. PMID 20086093. 
  20. ↑ "Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function". EMBO J. 30 (16): 3259–73. 2011. doi:10.1038/emboj.2011.234. PMID 21765395. 
  21. ↑ "The ESCRT-associated protein Alix recruits the ubiquitin ligase Nedd4-1 to facilitate HIV-1 release through the LYPXnL L domain motif". J. Virol. 84 (16): 8181–92. 2010. doi:10.1128/JVI.00634-10. PMID 20519395. 
  22. ↑ "Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation". J. Biol. Chem. 279 (25): 26754–61. 2004. doi:10.1074/jbc.M311802200. PMID 15060076. 
  23. ↑ "Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation". Am. J. Physiol. Renal Physiol. 281 (3): F469–77. 2001. doi:10.1152/ajprenal.2001.281.3.F469. PMID 11502596. 
  24. ↑ "The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels". FASEB J. 17 (1): 70–2. 2003. doi:10.1096/fj.02-0497fje. PMID 12424229. 
  25. ↑ "Respiratory distress and perinatal lethality in Nedd4-2-deficient mice". Nat Commun 2: 287. 2011. doi:10.1038/ncomms1284. PMID 21505443. Bibcode: 2011NatCo...2..287B. 
  26. ↑ 26.0 26.1 "Calcium activates Nedd4 E3 ubiquitin ligases by releasing the C2 domain-mediated auto-inhibition". J. Biol. Chem. 285 (16): 12279–88. 2010. doi:10.1074/jbc.M109.086405. PMID 20172859. 
  27. ↑ "Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins". EMBO Rep. 10 (5): 501–7. 2009. doi:10.1038/embor.2009.30. PMID 19343052. 
  28. ↑ "Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins". BioEssays 28 (6): 617–28. 2006. doi:10.1002/bies.20422. PMID 16700065. 
  29. ↑ "Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2". Proc. Natl. Acad. Sci. U.S.A. 107 (25): 11429–34. 2010. doi:10.1073/pnas.0911714107. PMID 20534535. Bibcode: 2010PNAS..10711429M. 
  30. ↑ "Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons". Proc. Natl. Acad. Sci. U.S.A. 106 (36): 15489–94. 2009. doi:10.1073/pnas.0904880106. PMID 19706893. Bibcode: 2009PNAS..10615489H. 
  31. ↑ "Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration". J. Neurosci. 32 (32): 10971–81. 2012. doi:10.1523/JNEUROSCI.1836-12.2012. PMID 22875931. 
  32. ↑ 32.0 32.1 "Impeded Nedd4-1-mediated Ras degradation underlies Ras-driven tumorigenesis". Cell Rep 7 (3): 871–82. May 2014. doi:10.1016/j.celrep.2014.03.045. PMID 24746824. 
  33. ↑ "Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 ligase, NEDD4-1, in the insulin-like growth factor-1 response". J. Biol. Chem. 288 (3): 1674–84. 2013. doi:10.1074/jbc.M112.416339. PMID 23195959. 
  34. ↑ "Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells". Nat. Immunol. 9 (12): 1356–63. 2008. doi:10.1038/ni.1670. PMID 18931680. 
  35. ↑ "Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development". Neuron 65 (3): 358–72. 2010. doi:10.1016/j.neuron.2010.01.007. PMID 20159449. 
  36. ↑ "Abnormal development of the neuromuscular junction in Nedd4-deficient mice". Dev. Biol. 330 (1): 153–66. 2009. doi:10.1016/j.ydbio.2009.03.023. PMID 19345204. 
  37. ↑ "The ubiquitin ligase Nedd4 regulates craniofacial development by promoting cranial neural crest cell survival and stem-cell like properties". Dev. Biol. 383 (2): 186–200. 2013. doi:10.1016/j.ydbio.2013.09.024. PMID 24080509. 
  38. ↑ "NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN". Cell 128 (1): 129–39. 2007. doi:10.1016/j.cell.2006.11.039. PMID 17218260. 
  39. ↑ "Ubiquitination regulates PTEN nuclear import and tumor suppression". Cell 128 (1): 141–56. 2007. doi:10.1016/j.cell.2006.11.040. PMID 17218261. 
  40. ↑ "The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization". Proc. Natl. Acad. Sci. U.S.A. 105 (25): 8585–90. 2008. doi:10.1073/pnas.0803233105. PMID 18562292. Bibcode: 2008PNAS..105.8585F. 
  41. ↑ "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. 2014. doi:10.1073/pnas.1400737111. PMID 25157163. Bibcode: 2014PNAS..11113205H. 
  42. ↑ "Disruption of E3 ligase NEDD4 in peripheral neurons interrupts axon outgrowth: Linkage to PTEN". Mol. Cell. Neurosci. 50 (2): 179–92. 2012. doi:10.1016/j.mcn.2012.04.006. PMID 22561198. 
  43. ↑ "E3 ligase Nedd4 promotes axon branching by downregulating PTEN". Neuron 65 (3): 341–57. 2010. doi:10.1016/j.neuron.2010.01.017. PMID 20159448. 
  44. ↑ "p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN". Cell Death Differ. 21 (1): 146–60. 2014. doi:10.1038/cdd.2013.141. PMID 24141722. 
  45. ↑ "SCF(β-TRCP)-mediated degradation of NEDD4 inhibits tumorigenesis through modulating the PTEN/Akt signaling pathway". Oncotarget 5 (4): 1026–37. 2014. doi:10.18632/oncotarget.1675. PMID 24657926. 
  46. ↑ "The Nedd4-like family of E3 ubiquitin ligases and cancer". Cancer Metastasis Rev. 26 (3–4): 587–604. 2007. doi:10.1007/s10555-007-9091-x. PMID 17726579. 
  47. ↑ "NEDD4: a promising target for cancer therapy". Curr Cancer Drug Targets 14 (6): 549–56. 2014. doi:10.2174/1568009614666140725092430. PMID 25088038. 
  48. ↑ "The histone deacetylase SIRT2 stabilizes Myc oncoproteins". Cell Death Differ. 20 (3): 503–14. 2013. doi:10.1038/cdd.2012.147. PMID 23175188. 
  49. ↑ 49.0 49.1 "Virus budding and the ESCRT pathway". Cell Host & Microbe 14 (3): 232–41. September 2013. doi:10.1016/j.chom.2013.08.012. PMID 24034610. 

External links

  • Overview of all the structural information available in the PDB for UniProt: P46934 (E3 ubiquitin-protein ligase NEDD4) at the PDBe-KB.



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