Detailed entry information

Protein Information (annotations from UniProt)

Database IDHIV0007547
UniProt IDP21580
Primary gene name(s)TNFAIP3
Synonym gene name(s)OTUD7C
Protein nameTumor necrosis factor alpha-induced protein 3
Protein functionUbiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities. Involved in immune and inflammatory responses signaled by cytokines, such as TNF-alpha and IL-1 beta, or pathogens via Toll-like receptors, TLRs through terminating NF-kappa-B activity. Essential component of a ubiquitin-editing protein complex, comprising also RNF11, ITCH and TAX1BP1, that ensures the transient nature of inflammatory signaling pathways. In cooperation with TAX1BP1 promotes disassembly of E2-E3 ubiquitin protein ligase complexes in IL-1R and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2 and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In cooperation with TAX1BP1 promotes ubiquitination of UBE2N and proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation, 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 NF-kappa-B. Deubiquitinates TRAF6 probably acting on 'Lys-63'-linked polyubiquitin. Upon T-cell receptor, TCR-mediated T-cell activation, deubiquitinates 'Lys-63'-polyubiquitin chains on MALT1 thereby mediating disassociation of the CBM, CARD11:BCL10:MALT1 and IKK complexes and preventing sustained IKK activation. Deubiquitinates NEMO/IKBKG; the function is facilitated by TNIP1 and leads to inhibition of NF-kappa-B activation. Upon stimulation by bacterial peptidoglycans, probably deubiquitinates RIPK2. Can also inhibit I-kappa-B-kinase, IKK through a non-catalytic mechanism which involves polyubiquitin; polyubiquitin promotes association with IKBKG and prevents IKK MAP3K7-mediated phosphorylation. Targets TRAF2 for lysosomal degradation. In vitro able to deubiquitinate 'Lys-11'-, 'Lys-48'- and 'Lys-63' polyubiquitin chains. Inhibitor of programmed cell death. Has a role in the function of the lymphoid system. Required for LPS-induced production of proinflammatory cytokines and IFN beta in LPS-tolerized macrophages. {ECO:0000269|PubMed:14748687, ECO:0000269|PubMed:15258597, ECO:0000269|PubMed:16684768, ECO:0000269|PubMed:17961127, ECO:0000269|PubMed:18164316, ECO:0000269|PubMed:18952128, ECO:0000269|PubMed:19494296, ECO:0000269|PubMed:22099304, ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:8692885, ECO:0000269|PubMed:9299557, ECO:0000269|PubMed:9882303}.
Subcellular locationCytoplasm. Nucleus. Lysosome.;
SUBCELLULAR LOCATION: A20p50: Cytoplasm.
ECO codeClick here for more information.
Amino acid sequence
FASTA format: P21580
Gene Ontology
(Biological Process)
Complete annatation
apoptotic process [GO:0006915];
B-1 B cell homeostasis [GO:0001922];
cellular response to hydrogen peroxide [GO:0070301];
cellular response to lipopolysaccharide [GO:0071222];
establishment of protein localization to vacuole [GO:0072666];
inflammatory response [GO:0006954];
negative regulation of B cell activation [GO:0050869];
negative regulation of bone resorption [GO:0045779];
negative regulation of CD40 signaling pathway [GO:2000349];
negative regulation of chronic inflammatory response [GO:0002677];
negative regulation of cyclin-dependent protein serine/threonine kinase activity [GO:0045736];
negative regulation of endothelial cell apoptotic process [GO:2000352];
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors [GO:1902042];
negative regulation of I-kappaB kinase/NF-kappaB signaling [GO:0043124];
negative regulation of inflammatory response [GO:0050728];
negative regulation of innate immune response [GO:0045824];
negative regulation of interleukin-1 beta production [GO:0032691];
negative regulation of interleukin-2 production [GO:0032703];
negative regulation of interleukin-6 production [GO:0032715];
negative regulation of NF-kappaB transcription factor activity [GO:0032088];
negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway [GO:0070429];
negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway [GO:0070433];
negative regulation of osteoclast proliferation [GO:0090291];
negative regulation of protein ubiquitination [GO:0031397];
negative regulation of smooth muscle cell proliferation [GO:0048662];
negative regulation of toll-like receptor 2 signaling pathway [GO:0034136];
negative regulation of toll-like receptor 3 signaling pathway [GO:0034140];
negative regulation of toll-like receptor 4 signaling pathway [GO:0034144];
negative regulation of toll-like receptor 5 signaling pathway [GO:0034148];
negative regulation of tumor necrosis factor production [GO:0032720];
negative regulation of type I interferon production [GO:0032480];
nucleotide-binding oligomerization domain containing signaling pathway [GO:0070423];
positive regulation of cellular protein catabolic process [GO:1903364];
positive regulation of hepatocyte proliferation [GO:2000347];
positive regulation of protein catabolic process [GO:0045732];
protein deubiquitination [GO:0016579];
protein deubiquitination involved in ubiquitin-dependent protein catabolic process [GO:0071947];
protein K11-linked deubiquitination [GO:0035871];
protein K48-linked deubiquitination [GO:0071108];
protein K48-linked ubiquitination [GO:0070936];
protein K63-linked deubiquitination [GO:0070536];
protein oligomerization [GO:0051259];
regulation of defense response to virus by host [GO:0050691];
regulation of germinal center formation [GO:0002634];
regulation of inflammatory response [GO:0050727];
regulation of tumor necrosis factor-mediated signaling pathway [GO:0010803];
regulation of vascular wound healing [GO:0061043];
response to molecule of bacterial origin [GO:0002237];
response to muramyl dipeptide [GO:0032495];
tolerance induction to lipopolysaccharide [GO:0072573]
Gene Ontology
(Molecular Function)
Complete annatation
DNA binding [GO:0003677];
K63-linked polyubiquitin binding [GO:0070530];
ligase activity [GO:0016874];
protease binding [GO:0002020];
protein self-association [GO:0043621];
thiol-dependent ubiquitin-specific protease activity [GO:0004843];
ubiquitin binding [GO:0043130];
ubiquitin-protein transferase activity [GO:0004842];
zinc ion binding [GO:0008270]
Gene Ontology
(Cellular Component)
Complete annatation
cytoplasm [GO:0005737];
cytosol [GO:0005829];
extracellular exosome [GO:0070062];
lysosome [GO:0005764];
nucleus [GO:0005634]
Protein-protein interaction112983
Phylogenetic treeP21580
HIV replication factor status Zhou et al., Cell. Host. Microbe., 2008
      unknown
Brass et al., Science, 2008
      unknown
Smith et al., J. Immunol, 2010
      unknown
Interferon-stimulated
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. CD32.687915586255522.05391259555654e-146.44928555004753e-13
AZA vs. DISU1.113509705755451.33689887890087e-050.00347455408630202
AZA vs. IL7-1.014716169774471.91210413391651e-070.000125309328741407
AZA vs. SAHA0.9116764105088330.0002079170521356310.0065430932022808
DISU vs. CD3-1.588432359524342.22842981771887e-050.000150633191876956
DISU vs. IL7-2.137764927476023.33066907387547e-163.86229509912867e-13
DISU vs. SAHA-0.1996173117159860.4927685343916850.819978901720075
DMSO vs. AZA-0.007461192213839680.9645460415300071
DMSO vs. CD3-2.709093601474073.21964677141295e-151.0063066101937e-13
DMSO vs. DISU-1.123621568204195.26559516622616e-060.0014170092706255
DMSO vs. IL7-0.999720858948394.1168626174759e-082.69833495471518e-05
DMSO vs. SAHA0.9134234117374610.0001204248425041850.00402421907179729
HIV vs. Mock in Activation0.0760110041186760.9142783562891180.999983755607037
HIV vs. Mock in Latency0.3895761924890260.2287180869835940.999834320637052
IL7 vs. CD3-3.6962495939451500
SAHA vs. CD3-1.800839089277299.07994918475374e-077.43667577251298e-06
SAHA vs. IL71.92264166441632.35367281220533e-141.01369325631952e-11
(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 -0.181133 0.208571
(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
1.026 1.073 1.036 1.021 1.074
(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
2EQE NMR - A=597-631.
2EQF NMR - A=758-790.
2EQG NMR - A=381-416.
2VFJ X-ray 3.2Å A/B/C/D=1-366.
3DKB X-ray 2.5Å A/B/C/D/E/F=1-370.
3OJ3 X-ray 2.5Å I/J/K/L/M/N/O/P=592-635.
3OJ4 X-ray 3.4Å C/F=592-635.
3VUW X-ray 1.9Å E/F/G=757-789.
3VUX X-ray 1.7Å E/F/G=757-790.
3VUY X-ray 1.9Å D/E/F=757-790.
3ZJD X-ray 1.8Å A/B=1-366.
3ZJE X-ray 1.8Å A/B=1-366.
3ZJF X-ray 2.2Å A/B=1-366.
3ZJG X-ray 1.9Å A/B=1-366.
4ZRH X-ray 2.7Å A/B/C/D/E/F=1-366.
4ZS5 X-ray 3.2Å A/B/C/D/E/F=1-366.
5DOD X-ray 2.5Å A/B/C/D/E/F=1-366.
5LRX X-ray 2.8Å A/C/E/F=1-366.

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

HIV Partner Interaction Type PubMed
Tat modulates 24742347

Metabolic/Signalling Pathway       (annotations from KEGG database)      top

Pathway Accession Number Description
hsa04064 NF-kappa B signaling pathway - Homo sapiens (human)
hsa04621 NOD-like receptor signaling pathway - Homo sapiens (human)
hsa04657 IL-17 signaling pathway - Homo sapiens (human)
hsa04668 TNF signaling pathway - Homo sapiens (human)
hsa05162 Measles - Homo sapiens (human)
hsa05169 Epstein-Barr virus infection - Homo sapiens (human)
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