Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0006007
UniProt IDP46934
Primary gene name(s)NEDD4
Synonym gene name(s)KIAA0093, NEDD4-1
Protein nameE3 ubiquitin-protein ligase NEDD4
Protein functionE3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Specifically ubiquitinates 'Lys-63' in target proteins, PubMed:23644597. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. Promotes ubiquitination of RAPGEF2. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2. Involved in the ubiquitination of ebola virus VP40 protein and this ubiquitination plays a role in facilitating viral budding. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1, PubMed:25631046. {ECO:0000269|PubMed:11598133, ECO:0000269|PubMed:17218260, ECO:0000269|PubMed:18305167, ECO:0000269|PubMed:18562292, ECO:0000269|PubMed:20086093, ECO:0000269|PubMed:21399620, ECO:0000269|PubMed:21765395, ECO:0000269|PubMed:23644597, ECO:0000269|PubMed:25631046}.
Subcellular locationCytoplasm {ECO:0000250}. Cell membrane {ECO:0000250};
Peripheral membrane protein {ECO:0000250}. Note=Recruited to the plasma membrane by GRB10. Once complexed with GRB10 and IGF1R, follows IGF1R internalization, remaining associated with early endosomes. Uncouples from IGF1R-containing endosomes before the sorting of the receptor to the lysosomal compartment, By similarity. May be recruited to exosomes by NDFIP1. {ECO:0000250, ECO:0000269|PubMed:18819914}.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: P46934
Gene Ontology
(Biological Process)
Complete annatation
adaptive immune response [GO:0002250];
blood vessel morphogenesis [GO:0048514];
cellular response to UV [GO:0034644];
development involved in symbiotic interaction [GO:0044111];
endocardial cushion development [GO:0003197];
glucocorticoid receptor signaling pathway [GO:0042921];
lysosomal transport [GO:0007041];
negative regulation of sodium ion transmembrane transporter activity [GO:2000650];
negative regulation of sodium ion transport [GO:0010766];
negative regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage [GO:0010768];
negative regulation of vascular endothelial growth factor receptor signaling pathway [GO:0030948];
neuromuscular junction development [GO:0007528];
neuron projection development [GO:0031175];
outflow tract morphogenesis [GO:0003151];
positive regulation of nucleocytoplasmic transport [GO:0046824];
positive regulation of phosphatidylinositol 3-kinase signaling [GO:0014068];
positive regulation of protein catabolic process [GO:0045732];
progesterone receptor signaling pathway [GO:0050847];
protein K63-linked ubiquitination [GO:0070534];
protein monoubiquitination [GO:0006513];
protein targeting to lysosome [GO:0006622];
protein ubiquitination [GO:0016567];
protein ubiquitination involved in ubiquitin-dependent protein catabolic process [GO:0042787];
receptor catabolic process [GO:0032801];
receptor internalization [GO:0031623];
regulation of dendrite morphogenesis [GO:0048814];
regulation of ion transmembrane transport [GO:0034765];
regulation of macroautophagy [GO:0016241];
regulation of membrane potential [GO:0042391];
regulation of potassium ion transmembrane transporter activity [GO:1901016];
regulation of synapse organization [GO:0050807];
response to calcium ion [GO:0051592];
T cell activation [GO:0042110];
transmission of virus [GO:0019089];
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway [GO:0043162]
Gene Ontology
(Molecular Function)
Complete annatation
beta-2 adrenergic receptor binding [GO:0031698];
ligase activity [GO:0016874];
phosphoserine binding [GO:0050815];
phosphothreonine binding [GO:0050816];
proline-rich region binding [GO:0070064];
protein domain specific binding [GO:0019904];
RNA polymerase binding [GO:0070063];
sodium channel inhibitor activity [GO:0019871];
ubiquitin binding [GO:0043130];
ubiquitin protein ligase activity [GO:0061630]
Gene Ontology
(Cellular Component)
Complete annatation
apicolateral plasma membrane [GO:0016327];
cell cortex [GO:0005938];
chromatin [GO:0000785];
cytoplasm [GO:0005737];
cytosol [GO:0005829];
extracellular exosome [GO:0070062];
Golgi apparatus [GO:0005794];
membrane raft [GO:0045121];
microvillus [GO:0005902];
nucleus [GO:0005634];
perinuclear region of cytoplasm [GO:0048471];
plasma membrane [GO:0005886];
ubiquitin ligase complex [GO:0000151]
Protein-protein interaction110811
Phylogenetic treeP46934
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
Brass et al., Science, 2008
Smith et al., J. Immunol, 2010
gene status
Lu et al., J. Virol., 2011
      Folds changes 8h: unknown; Folds changes 16h: unknown; Tested: unknown;
Schoggins JW and Rice CM, Curr. Opin. Virol., 2011
      Targeted viruses: unknown
      Viral life cycle: unknown
      Mechanism related to antiviral activity: unknown
Anti-viral restriction factor Liu et al., Retrovirology, 2011
      unknown (Triplicates)

Gene Expression Profile       top

            Up-regulated;            Down-regulated

For brief introduction to each study, please go to the help page.

Gene expression during HIV latency

(1). Mohammadi et al., PLoS Pathog., 2014

Differentially expressed transcripts (Pairwise) during latency and subsequent viral reactivation using several agents - Primary CD4+ T-cell based model

DMSO: Dimethyl suloxyde (negative control) - 0.0033% final
SAHA: Vorinostat (Histone deacetylase inhibitor) - 0.5 μM
CD3: TCR Stimulation by IL-2+ antiCD3/anti-CD28 antibodies
IL7: Interleukin-7 based stimulation
DISU: Disulfiram (alcohol dehydrogenase inhibitor) - 0.5 μM
AZA: 5-azacytidine (AZA; DNA methylation inhibitor) - 1 μM
Experimental Condition Log2 Fold Change P value Adjusted P value
AZA vs. CD30.06514560874367230.8424386512573110.89417150364438
AZA vs. DISU-0.1810562092277580.4757058678256180.929581313404636
AZA vs. IL7-0.1152341493528380.5524433162888720.999311006273513
AZA vs. SAHA0.2498901158939010.3077786464747550.68037180187131
DISU vs. CD3-0.2593914600275350.4746056075220520.602560846271996
DISU vs. IL70.05708525036449610.8213300913967870.961667592689605
DISU vs. SAHA0.4314734967272540.1402523083576240.480723797875313
DMSO vs. AZA-0.0470346756672440.7987886628783751
DMSO vs. CD3-0.1222790274538220.7024502501678940.781954360618564
DMSO vs. DISU0.1325169078741320.5883927944355630.934701463289767
DMSO vs. IL7-0.06120521123202290.7354753749284150.946333083680773
DMSO vs. SAHA0.2887024104307960.2225592599191490.567929327165846
HIV vs. Mock in Activation0.1292485049967320.8363508094923170.999983755607037
HIV vs. Mock in Latency-0.05187633743994010.7547311883516790.999834320637052
IL7 vs. CD3-0.1716158717039050.5936443575345830.710835827861358
SAHA vs. CD30.1585980890371730.6538110648909180.742045897365233
SAHA vs. IL70.3599268045463210.1411675930992780.354187799330645
(2). Iglesias-Ussel et al., J. Virol., 2013

Up and Downregulated transcripts during Latency (Latently infected CD4+ T cells vs Uninfected)- Primary CD4+Tcell based model
Log2 Fold Change P Value
unknown unknown

Gene expression during HIV infection and replication

(1). Imbeault et al., PloS Pathog., 2012

Transcriptomic profiling of HIV-1 infected CD4+ T cells - Primary CD4+ T cells
Experiment type Log2 Fold Change P Value Adjusted P Value
Infected vs. Mock unknown unknown unknown
Infected vs. Bystander unknown unknown unknown
(2). Lefebvre et al., J. Virol., 2011

Transcriptome analysis of T-cell line (Sup T1)
Log2 Fold Change unknown
(3). Li et al., J. Immunol., 2013

Lymphatic tissue
Acute Fold Change Acute P Value Asymt Fold Change Asypt P Value AIDS Fold Change AIDS P Value
unknown unknown unknown unknown unknown unknown
(4). Chang et al., MBio., 2011

Transcriptome analysis of T-cell line (Sup T1)

Derived from Sherrill-Mix et al., BMC Retrovirol., 2015 cross validation
Up-regulated (True) unknown
(5). Sherrill-Mix et al., BMC Retrovirol., 2015

Deep RNA-seq analysis of primary human T cell infected with low passage HIV isolate HIV89.6 - Primary CD4+ T cell based
Test Status Log2 Fold Change P Value
OK 0.111854 0.532659
(6). Rotger et al., PLoS Pathog., 2010

Genome-wide mRNA expression of CD4+ T cells from HIV-infected patient
(Genes differentially expressed (at adjusted p<0.01) according to the empirical Bayes approach)
Log2 Fold Change P Value
unknown unknown

Proteomic/Transcriptomics studies indicating differentially expressed genes mediated by HIV

(1). Greenwood et al., Elife, 2016

Activated (CD3/CD28) Primary human CD4+ T cells infected with pNL4-3-dE-EGFP. The table shows the complete (unfiltered) TMT (tandem mass tag)-based proteomic time course dataset
6 h 24 h 48 h 72 h RTi
1.072 1.352 1.693 2.034 1.423
(2). Navare et al., Virology, 2012

SUP-T1 cell line
FC-4hpi P-value FC-8hpi P-value FC-20hpi P-value Category
unknown unknown unknown unknown unknown unknown unknown
(3). Hyrcza et al., J. Virolo., 2007

Primary human CD4+ and CD8+ T Cells
Affymetrix Prob ID Fold Change In CD8? Category
unknown unknown unknown unknown

Protein Overview       top

Drug-protein Interaction       (annotations from DrugBank)      top

not found

Protein Secondary Structure       (annotations from PDB)      top

PDB Accession Method Resolution Chain Structure Preview
2KPZ NMR - A=834-878.
2KQ0 NMR - A=834-878.
2M3O NMR - W=838-877.
2XBB X-ray 2.6Å A/B=938-1319.
2XBF X-ray 2.5Å A=938-1319.
3B7Y X-ray 1.8Å A/B=517-571.
4BBN X-ray 2.5Å A=938-1319.
4BE8 X-ray 3.0Å A=938-1319.
4N7F X-ray 1.1Å A/B=841-874.
4N7H X-ray 1.7Å A=840-872.
5AHT NMR - A=838-877.
5C7J X-ray 3.0Å A/B=939-1319.
5C91 X-ray 2.4Å A=938-1312.

HIV-1 Interaction       (annotations from NCBI HIV-1 Interaction Database)      top

HIV Partner Interaction Type PubMed
Vif binds 15013426
Envelope surface glycoprotein gp160; precursor upregulated by 24614057
Nef co-localizes with 23071112
Pr55(Gag) binds 20519395
Pr55(Gag) ubiquitinated by 11087859
p6 interacts with 20519395
Envelope surface glycoprotein gp120 upregulated by 24614057
capsid upregulated by 24614057
p6 ubiquitinated by 11087859
HIV-1 virus replication enhanced by expression of human gene 18854154
Pr55(Gag) interacts with 20519395
Pr55(Gag) upregulated by 24614057

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04120 Ubiquitin mediated proteolysis - Homo sapiens (human)
hsa04144 Endocytosis - Homo sapiens (human)
hsa04530 Tight junction - Homo sapiens (human)
hsa05169 Epstein-Barr virus infection - Homo sapiens (human)