Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0005380
UniProt IDQ96J02
Primary gene name(s)ITCH
Synonym gene name(s)unknown
Protein nameE3 ubiquitin-protein ligase Itchy homolog
Protein functionActs as an E3 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. It catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation. It is involved in the control of inflammatory signaling pathways. Is an essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways. Promotes the association of the complex after TNF stimulation. Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1. Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways. Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response. Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages. Critical regulator of T-helper, TH2 cytokine development through its ability to induce JUNB ubiquitination and degradation, By similarity. Ubiquitinates SNX9. Ubiquitinates CXCR4 and HGS/HRS and regulates sorting of CXCR4 to the degradative pathway. It is involved in the negative regulation of MAVS-dependent cellular antiviral responses. Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation. Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP. Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID. Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination. Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1, PubMed:25631046. {ECO:0000250|UniProtKB:Q8C863, ECO:0000269|PubMed:14602072, ECO:0000269|PubMed:16387660, ECO:0000269|PubMed:17028573, ECO:0000269|PubMed:18628966, ECO:0000269|PubMed:18718448, ECO:0000269|PubMed:18718449, ECO:0000269|PubMed:19131965, ECO:0000269|PubMed:19592251, ECO:0000269|PubMed:19881509, ECO:0000269|PubMed:20068034, ECO:0000269|PubMed:20392206, ECO:0000269|PubMed:23146885, ECO:0000269|PubMed:25631046}.
Subcellular locationCell membrane. Cytoplasm {ECO:0000250}. Nucleus. Note=Associates with endocytic vesicles. May be recruited to exosomes by NDFIP1.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: Q96J02
Gene Ontology
(Biological Process)
Complete annatation
apoptotic process [GO:0006915];
defense response to virus [GO:0051607];
inflammatory response [GO:0006954];
innate immune response [GO:0045087];
negative regulation of apoptotic process [GO:0043066];
negative regulation of defense response to virus [GO:0050687];
negative regulation of JNK cascade [GO:0046329];
negative regulation of NF-kappaB transcription factor activity [GO:0032088];
negative regulation of type I interferon production [GO:0032480];
Notch signaling pathway [GO:0007219];
nucleotide-binding oligomerization domain containing signaling pathway [GO:0070423];
protein K29-linked ubiquitination [GO:0035519];
protein K48-linked ubiquitination [GO:0070936];
protein K63-linked ubiquitination [GO:0070534];
protein ubiquitination [GO:0016567];
protein ubiquitination involved in ubiquitin-dependent protein catabolic process [GO:0042787];
regulation of cell growth [GO:0001558];
regulation of protein deubiquitination [GO:0090085];
ubiquitin-dependent protein catabolic process [GO:0006511];
viral entry into host cell [GO:0046718]
Gene Ontology
(Molecular Function)
Complete annatation
CXCR chemokine receptor binding [GO:0045236];
ligase activity [GO:0016874];
ribonucleoprotein complex binding [GO:0043021];
ubiquitin-like protein transferase activity [GO:0019787];
ubiquitin protein ligase activity [GO:0061630];
ubiquitin-protein transferase activity [GO:0004842]
Gene Ontology
(Cellular Component)
Complete annatation
cell cortex [GO:0005938];
cytoplasm [GO:0005737];
cytoplasmic vesicle [GO:0031410];
cytosol [GO:0005829];
extracellular exosome [GO:0070062];
membrane [GO:0016020];
nucleus [GO:0005634];
plasma membrane [GO:0005886]
Protein-protein interaction123747
Phylogenetic treeQ96J02
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. CD30.3751400341459120.2520514545699020.364754634976242
AZA vs. DISU0.3567746582148020.162979729976440.747228926355439
AZA vs. IL70.03252222274540820.8656905712323830.999311006273513
AZA vs. SAHA-0.3724720953935230.1277390824610320.454672710511829
DISU vs. CD3-0.03083267153616220.9327044570038690.956174305282666
DISU vs. IL7-0.333092806643640.1900359228571020.563990378080262
DISU vs. SAHA-0.7285818659471530.01322105657798590.124611972286945
DMSO vs. AZA-0.09817758186571730.5581937476517041
DMSO vs. CD3-0.4824934449864070.1317474434518990.21389969130325
DMSO vs. DISU-0.4561281089810550.06441507434692620.482161876337257
DMSO vs. IL70.1376117915709210.4442931088151070.866592093088172
DMSO vs. SAHA-0.2823190506159460.2318594111165060.578631095369575
HIV vs. Mock in Activation0.08949159686237180.8857946586054590.999983755607037
HIV vs. Mock in Latency0.1218707673360890.4602982191586710.999834320637052
IL7 vs. CD3-0.3344233620199760.2977714732093730.435293319337104
SAHA vs. CD3-0.7729154163809390.02951194195534930.0639185060746069
SAHA vs. IL7-0.4092232385247350.09351462306032810.276454094530572
(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 -0.0714753 0.686625
(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
1.034 1.084 1.088 1.126 1.114
(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
2DMV NMR - A=328-357.
2KYK NMR - A=359-392.
2NQ3 X-ray 1.8Å A=1-155.
2P4R X-ray 2.0Å T=246-270.
2YSF NMR - A=480-512.
3TUG X-ray 2.2Å A=524-903.
4ROF X-ray 2.0Å A/B=436-474.
5C7M X-ray 3.0Å A=524-899.
5CQ2 X-ray 1.4Å A=433-521.
5DWS X-ray 1.6Å A/C/E/G=436-474.
5DZD X-ray 1.5Å A/B=475-514.

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

HIV Partner Interaction Type PubMed
Vif binds 15013426
Nef co-localizes with 23071112
Nef mediated by 24489825
Nef enhances 24489825

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04120 Ubiquitin mediated proteolysis - Homo sapiens (human)
hsa04144 Endocytosis - Homo sapiens (human)
hsa04668 TNF signaling pathway - Homo sapiens (human)
hsa04932 Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)