InnateDB: Systems Biology of the Innate Immune Response

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

IDBP-97035

tumor necrosis factor, alpha-induced protein 3

IDBP-387496

tumor necrosis factor, alpha-induced protein 3

IDBP-387497

tumor necrosis factor, alpha-induced protein 3

IDBP-387498

tumor necrosis factor, alpha-induced protein 3

IDBP-808133

tumor necrosis factor, alpha-induced protein 3

IDBP-808137

tumor necrosis factor, alpha-induced protein 3

IDBP-808164

tumor necrosis factor, alpha-induced protein 3

IDBP-808166

tumor necrosis factor, alpha-induced protein 3

IDBP-808169

tumor necrosis factor, alpha-induced protein 3

IDBP-808172

tumor necrosis factor, alpha-induced protein 3

IDBP-808178

tumor necrosis factor, alpha-induced protein 3

Protein Structure

Useful resources

Stemformatics EHFPI ImmGen

InnateDB Annotation

Summary

PMID 18268035

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.

PMID 18342009

TNFAIP3 restricts NOD2 triggered signals by deubiquitinating RIPK2.

PMID 16306043

TNFAIP3 negatively regulates the RIG-I antiviral state by blocking IRF- and NF-kappaB-mediated gene expression.

PMID 18349075

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).

PMID 15258597

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.

PMID 17709380

TNFAIP3 is phosphorylated by IKBKB and this increases the ability of TNFAIP3 to inhibit the NF-kappaB signalling pathway.

PMID 19008218

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.

PMID 20304918

TNFAIP3 (A20) and TAX1BP1 inhibit antiviral signaling by targeting TBK1/IKKi kinases and disrupting a TRAF3-TBK1-IKKi signalling complex.

PMID 20798608

TNFAIP3 and TRAF6 differentially regulate TLR4-induced autophagy during inflammatory responses by modulating K63-linked ubiquitination of BECN1 (Beclin 1).

PMID 21119682

TNFAIP3 is a deubiquitinase that counteracts E3 ligases and therefore play a prominent role in the down-regulation of NF-κB signalling and homeostasis.

PMID 21220427

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.

PMID 22031828

TNFAIP3 promotes intestinal epithelial barrier integrity and inhibits LPS-induced loss of the tight junction protein occludin. (Demonstrated in mice)

PMID 26642243

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

PMID 21220427

[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.

PMID 22031828

[Mus musculus] Tnfaip3 promotes intestinal epithelial barrier integrity and inhibits LPS-induced loss of the tight junction protein occludin.

PMID 24023826

[Mus musculus] Tnfaip3 is regulated by both Nf-κB and p38-dependent Cebpb in response to LPS in macrophages.

PMID 25683052

[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.

PMID 25609235

[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