Homo sapiens Gene: TNFAIP3
Summary
InnateDB Gene IDBG-97033.6
Last Modified 2014-10-13 [Report errors or provide feedback]
Gene Symbol TNFAIP3
Gene Name tumor necrosis factor, alpha-induced protein 3
Synonyms A20; OTUD7C; TNFA1P2;
Species Homo sapiens
Ensembl Gene ENSG00000118503
Encoded Proteins
tumor necrosis factor, alpha-induced protein 3
tumor necrosis factor, alpha-induced protein 3
tumor necrosis factor, alpha-induced protein 3
tumor necrosis factor, alpha-induced protein 3
tumor necrosis factor, alpha-induced protein 3
tumor necrosis factor, alpha-induced protein 3
tumor necrosis factor, alpha-induced protein 3
tumor necrosis factor, alpha-induced protein 3
tumor necrosis factor, alpha-induced protein 3
tumor necrosis factor, alpha-induced protein 3
tumor necrosis factor, alpha-induced protein 3
Protein Structure
Useful resources Stemformatics EHFPI ImmGen
InnateDB Annotation
Summary
TNFAIP3 restricts TLR signals by restricting ubiquitination of TRAF6 and restricts MyD88-independent TLR signals by inhibiting Toll/interleukin 1 receptor domain-containing adaptor inducing interferon (IFN) beta (TICAM1)-dependent nuclear factor kappaB signals but not IFN response factor 3 signalling.
TNFAIP3 restricts NOD2 triggered signals by deubiquitinating RIPK2.
TNFAIP3 negatively regulates the RIG-I antiviral state by blocking IRF- and NF-kappaB-mediated gene expression.
TNFAIP3 negatively regulates BCL10- and CARMA3-mediated activation of NF-kappaB by means of its deubiquitylation activity and preventing assembly of the complex containing CARMA3, BCL10 and IKBKG (NEMO).
TNFAIP3 removes lysine-63 linked ubiquitin chains from RIPK1 and polyubiquitinates RIPK1 with K48-linked ubiquitin chains, targeting it for proteosomal degradation, and hence down-regulating NF-kappaB signalling pathway.
TNFAIP3 is phosphorylated by IKBKB and this increases the ability of TNFAIP3 to inhibit the NF-kappaB signalling pathway.
TNFAIP3 is an early NF-kappaB-responsive gene that encodes a ubiquitin-editing protein that is involved in the negative feedback regulation of NF-kappaB signalling and thus is a central gatekeeper in inflammation and immunity.
TNFAIP3 (A20) and TAX1BP1 inhibit antiviral signaling by targeting TBK1/IKKi kinases and disrupting a TRAF3-TBK1-IKKi signalling complex.
TNFAIP3 and TRAF6 differentially regulate TLR4-induced autophagy during inflammatory responses by modulating K63-linked ubiquitination of BECN1 (Beclin 1).
TNFAIP3 is a deubiquitinase that counteracts E3 ligases and therefore play a prominent role in the down-regulation of NF-κB signalling and homeostasis.
TNFAIP3 expression and TNFAIP3-IRAK1interaction are important for endotoxin tolerance. TNFAIP3 over-expression inhibits LPS-induced activation of NFKB, and is mechanistically linked to endotoxin tolerance through the reprogramming of TLR4 signalling.
TNFAIP3 promotes intestinal epithelial barrier integrity and inhibits LPS-induced loss of the tight junction protein occludin. (Demonstrated in mice)
Haploinsufficiency of A20 (HA20) is caused by high-penetrance loss-of-function germline mutations in TNFAIP3 with increased degradation of NFKBIA, nuclear translocation of RELA, increased expression of NFκB mediated proinflammatory cytokines, and defective deubiquitinating activity.
InnateDB Annotation from Orthologs
Summary
[Mus musculus] Tnfaip3 expression and Tnfaip3-Irak1interaction are important for endotoxin tolerance. Tnfaip3 overexpression inhibits LPS-induced activation of NFKB, and is mechanistically linked to endotoxin tolerance through the reprogramming of Tlr4 signaling.
[Mus musculus] Tnfaip3 promotes intestinal epithelial barrier integrity and inhibits LPS-induced loss of the tight junction protein occludin.
[Mus musculus] Tnfaip3 is regulated by both Nf-κB and p38-dependent Cebpb in response to LPS in macrophages.
[Mus musculus] Mirlet7f and its target Tnfaip3 regulate immune responses to Mycobacterium tuberculosis and control bacterial burden by augmenting the production of Tnf and Il1b.
[Mus musculus] Sqstm1 captures Tnfaip3, an NFkB inhibitor, and sequesters it in the autophagosome. This allows macrophages to release chemokines that recruit neutrophils and boost antifungal immunity.
Entrez Gene
Summary This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded by this gene is a zinc finger protein and ubiqitin-editing enzyme, and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. The encoded protein, which has both ubiquitin ligase and deubiquitinase activities, is involved in the cytokine-mediated immune and inflammatory responses. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2012]
Gene Information
Type Protein coding
Genomic Location Chromosome 6:137867188-137883312
Strand Forward strand
Band q23.3
Transcripts
ENST00000237289 ENSP00000237289
ENST00000421450 ENSP00000393577
ENST00000420009 ENSP00000401562
ENST00000433680 ENSP00000409845
ENST00000485192
ENST00000612899 ENSP00000481570
ENST00000614035 ENSP00000481122
ENST00000614451 ENSP00000481199
ENST00000619035 ENSP00000478438
ENST00000620204 ENSP00000481454
ENST00000621150 ENSP00000484332
ENST00000615468 ENSP00000479556
Interactions
Number of Interactions This gene and/or its encoded proteins are associated with 130 experimentally validated interaction(s) in this database.
They are also associated with 20 interaction(s) predicted by orthology.
Experimentally validated
Total 130 [view]
Protein-Protein 124 [view]
Protein-DNA 6 [view]
Protein-RNA 0
DNA-DNA 0
RNA-RNA 0
DNA-RNA 0
Predicted by orthology
Total 20 [view]
Gene Ontology

Molecular Function
Accession GO Term
GO:0002020 protease binding
GO:0003677 DNA binding
GO:0004221 ubiquitin thiolesterase activity
GO:0004842 ubiquitin-protein transferase activity
GO:0004843 ubiquitin-specific protease activity
GO:0005515 protein binding
GO:0008270 zinc ion binding
GO:0016874 ligase activity
GO:0019900 kinase binding
GO:0043130 ubiquitin binding
GO:0043621 protein self-association
Biological Process
GO:0001922 B-1 B cell homeostasis
GO:0002237 response to molecule of bacterial origin
GO:0002634 regulation of germinal center formation
GO:0002677 negative regulation of chronic inflammatory response
GO:0006508 proteolysis
GO:0006915 apoptotic process
GO:0006954 inflammatory response
GO:0016579 protein deubiquitination
GO:0031397 negative regulation of protein ubiquitination
GO:0032088 negative regulation of NF-kappaB transcription factor activity
GO:0032480 negative regulation of type I interferon production
GO:0032495 response to muramyl dipeptide
GO:0032691 negative regulation of interleukin-1 beta production
GO:0032703 negative regulation of interleukin-2 production
GO:0032715 negative regulation of interleukin-6 production
GO:0032720 negative regulation of tumor necrosis factor production
GO:0034136 negative regulation of toll-like receptor 2 signaling pathway
GO:0034140 negative regulation of toll-like receptor 3 signaling pathway
GO:0034144 negative regulation of toll-like receptor 4 signaling pathway
GO:0034148 negative regulation of toll-like receptor 5 signaling pathway
GO:0035871 protein K11-linked deubiquitination
GO:0035872 nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway
GO:0043124 negative regulation of I-kappaB kinase/NF-kappaB signaling
GO:0045087 innate immune response (InnateDB)
GO:0045732 positive regulation of protein catabolic process
GO:0045736 negative regulation of cyclin-dependent protein serine/threonine kinase activity
GO:0045779 negative regulation of bone resorption
GO:0045824 negative regulation of innate immune response
GO:0048662 negative regulation of smooth muscle cell proliferation
GO:0050691 regulation of defense response to virus by host
GO:0050728 negative regulation of inflammatory response
GO:0050869 negative regulation of B cell activation
GO:0051259 protein oligomerization
GO:0060548 negative regulation of cell death
GO:0061043 regulation of vascular wound healing
GO:0070301 cellular response to hydrogen peroxide
GO:0070423 nucleotide-binding oligomerization domain containing signaling pathway
GO:0070429 negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway
GO:0070433 negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway
GO:0070536 protein K63-linked deubiquitination
GO:0070936 protein K48-linked ubiquitination
GO:0071108 protein K48-linked deubiquitination
GO:0071222 cellular response to lipopolysaccharide
GO:0072573 tolerance induction to lipopolysaccharide
GO:0090291 negative regulation of osteoclast proliferation
GO:1902042 negative regulation of extrinsic apoptotic signaling pathway via death domain receptors
GO:2000347 positive regulation of hepatocyte proliferation
GO:2000349 negative regulation of CD40 signaling pathway
GO:2000352 negative regulation of endothelial cell apoptotic process
Cellular Component
GO:0005634 nucleus
GO:0005737 cytoplasm
GO:0005764 lysosome
GO:0005813 centrosome
GO:0005829 cytosol
GO:0070062 extracellular vesicular exosome
Orthologs
Species
Mus musculus
Bos taurus
Gene ID
Gene Order
Method
Confidence
Comments
Non-SSD Ortholog
Possible paralog/unusual divergence/ gene prediction error
Not yet available
Non-SSD Ortholog
Possible paralog/unusual divergence/ gene prediction error
Pathways
NETPATH
TNFalpha pathway
REACTOME
Innate Immune System pathway
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways pathway
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways pathway
NOD1/2 Signaling Pathway pathway
Immune System pathway
Negative regulators of RIG-I/MDA5 signaling pathway
KEGG
NOD-like receptor signaling pathway pathway
INOH
PID BIOCARTA
Tnfr2 signaling pathway [Biocarta view]
Cd40l signaling pathway [Biocarta view]
PID NCI
CD40/CD40L signaling
TNF receptor signaling pathway
Canonical NF-kappaB pathway
Cross-References
SwissProt
TrEMBL
UniProt Splice Variant
Entrez Gene
UniGene Hs.211600 Hs.715063
RefSeq NM_001270507 NM_001270508 NM_006290 XM_005267119
HUGO
OMIM
CCDS CCDS5187
HPRD 01857
IMGT
EMBL
GenPept
RNA Seq Atlas