InnateDB: Systems Biology of the Innate Immune Response

Mus musculus Protein: Tnfaip3

Summary

InnateDB Protein

IDBP-135794.6

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

Tnfaip3

Protein Name

tumor necrosis factor, alpha-induced protein 3

Synonyms

A20; Tnfip3;

Species

Mus musculus

Ensembl Protein

ENSMUSP00000019997

InnateDB Gene

IDBG-135792 (Tnfaip3)

Protein Structure

UniProt Annotation

Function

Ubiquitin-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:0000269PubMed:10385526, ECO:0000269PubMed:11389905, ECO:0000269PubMed:15334086, ECO:0000269PubMed:18342009, ECO:0000269PubMed:20185725, ECO:0000269PubMed:23609450}.

Subcellular Localization

Cytoplasm {ECO:0000250}. Nucleus {ECO:0000250}. Lysosome {ECO:0000250}.

Disease Associations

Tissue Specificity

Found in most tissues during development. Strikingly high levels are found in lymphoid organs, including the thymus, spleen, and gut-associated lymphoid tissue. Constitutively expressed in immature and mature thymocyte subpopulations as well as in resting peripheral T-cells; activation of these leads to down-regulation.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 38 experimentally validated interaction(s) in this database.
They are also associated with 67 interaction(s) predicted by orthology.

Experimentally validated
Total	38 [view]
Protein-Protein	30 [view]
Protein-DNA	8 [view]
Protein-RNA	0
DNA-DNA	0
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	67 [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:0002315	marginal zone B cell differentiation
GO:0002632	negative regulation of granuloma formation
GO:0002634	regulation of germinal center formation
GO:0002637	regulation of immunoglobulin production
GO:0002677	negative regulation of chronic inflammatory response
GO:0006508	proteolysis
GO:0006915	apoptotic process
GO:0006954	inflammatory response
GO:0009611	response to wounding
GO:0010507	negative regulation of autophagy
GO:0016579	protein deubiquitination
GO:0031397	negative regulation of protein ubiquitination
GO:0032088	negative regulation of NF-kappaB transcription factor activity
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:0034115	negative regulation of heterotypic cell-cell adhesion
GO:0034140	negative regulation of toll-like receptor 3 signaling pathway
GO:0034148	negative regulation of toll-like receptor 5 signaling pathway
GO:0035871	protein K11-linked deubiquitination
GO:0043124	negative regulation of I-kappaB kinase/NF-kappaB signaling
GO:0045087	innate immune response (InnateDB)
GO:0045088	regulation of innate immune response
GO:0045732	positive regulation of protein catabolic process
GO:0045736	negative regulation of cyclin-dependent protein serine/threonine kinase activity
GO:0045824	negative regulation of innate immune response
GO:0048662	negative regulation of smooth muscle cell proliferation
GO:0050728	negative regulation of inflammatory response
GO:0050869	negative regulation of B cell activation
GO:0060548	negative regulation of cell death
GO:0070301	cellular response to hydrogen peroxide
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: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