TNFAIP3

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.

TNF alpha induced protein 3

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 pro-inflammatory cytokines and IFN beta in LPS-tolerized macrophages.

Biological Process apoptotic processSource:UniProtKB-KW
Biological Process B-1 B cell homeostasisSource:BHF-UCL
Biological Process cell migrationSource:GO_Central1 Publication
Biological Process cellular response to hydrogen peroxideSource:UniProtKB
Biological Process cellular response to lipopolysaccharideSource:BHF-UCL3 Publications
Biological Process cytoskeleton organizationSource:GO_Central1 Publication
Biological Process establishment of protein localization to vacuoleSource:Ensembl
Biological Process inflammatory responseSource:UniProtKB-KW
Biological Process negative regulation of B cell activationSource:BHF-UCL
Biological Process negative regulation of bone resorptionSource:BHF-UCL1 Publication
Biological Process negative regulation of CD40 signaling pathwaySource:BHF-UCL1 Publication
Biological Process negative regulation of chronic inflammatory responseSource:Ensembl
Biological Process negative regulation of cyclin-dependent protein serine/threonine kinase activitySource:Ensembl
Biological Process negative regulation of endothelial cell apoptotic processSource:BHF-UCL1 Publication
Biological Process negative regulation of extrinsic apoptotic signaling pathway via death domain receptorsSource:BHF-UCL1 Publication
Biological Process negative regulation of I-kappaB kinase/NF-kappaB signalingSource:UniProtKB1 Publication
Biological Process negative regulation of inflammatory responseSource:BHF-UCL
Biological Process negative regulation of innate immune responseSource:UniProtKB
Biological Process negative regulation of interleukin-1 beta productionSource:MGI1 Publication
Biological Process negative regulation of interleukin-2 productionSource:BHF-UCL1 Publication
Biological Process negative regulation of interleukin-6 productionSource:BHF-UCL
Biological Process negative regulation of NF-kappaB transcription factor activitySource:BHF-UCL1 Publication
Biological Process negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathwaySource:Ensembl
Biological Process negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathwaySource:Ensembl
Biological Process negative regulation of osteoclast proliferationSource:BHF-UCL1 Publication
Biological Process negative regulation of protein ubiquitinationSource:BHF-UCL1 Publication
Biological Process negative regulation of smooth muscle cell proliferationSource:BHF-UCL1 Publication
Biological Process negative regulation of toll-like receptor 2 signaling pathwaySource:BHF-UCL1 Publication
Biological Process negative regulation of toll-like receptor 3 signaling pathwaySource:BHF-UCL1 Publication
Biological Process negative regulation of toll-like receptor 4 signaling pathwaySource:BHF-UCL1 Publication
Biological Process negative regulation of toll-like receptor 5 signaling pathwaySource:Ensembl
Biological Process negative regulation of tumor necrosis factor productionSource:BHF-UCL
Biological Process nucleotide-binding oligomerization domain containing signaling pathwaySource:Reactome
Biological Process positive regulation of hepatocyte proliferationSource:Ensembl
Biological Process positive regulation of protein catabolic processSource:BHF-UCL1 Publication
Biological Process positive regulation of Wnt signaling pathwaySource:GO_Central1 Publication
Biological Process protein deubiquitinationSource:BHF-UCL1 Publication
Biological Process protein deubiquitination involved in ubiquitin-dependent protein catabolic processSource:GO_Central1 Publication
Biological Process protein K11-linked deubiquitinationSource:UniProtKB1 Publication
Biological Process protein K29-linked deubiquitinationSource:GO_Central1 Publication
Biological Process protein K33-linked deubiquitinationSource:GO_Central1 Publication
Biological Process protein K48-linked deubiquitinationSource:UniProtKB1 Publication
Biological Process protein K48-linked ubiquitinationSource:UniProtKB1 Publication
Biological Process protein K63-linked deubiquitinationSource:UniProtKB1 Publication
Biological Process regulation of defense response to virus by hostSource:BHF-UCL1 Publication
Biological Process regulation of germinal center formationSource:BHF-UCL
Biological Process regulation of tumor necrosis factor-mediated signaling pathwaySource:Reactome
Biological Process regulation of vascular wound healingSource:BHF-UCL1 Publication
Biological Process response to molecule of bacterial originSource:BHF-UCL1 Publication
Biological Process response to muramyl dipeptideSource:Ensembl
Biological Process tolerance induction to lipopolysaccharideSource:BHF-UCL1 Publication

Cytoplasm
Nucleus
Lysosome
A20p50
Cytoplasm

Autoinflammatory syndrome, familial, Behcet-like 1 (AIFBL1):
An autosomal dominant, autoinflammatory disorder with early onset, characterized by ulceration of mucosal surfaces, particularly in the oral and genital areas. Additional variable features include skin rash, uveitis, and polyarthritis.

Proteolytically cleaved by MALT1 upon TCR stimulation; disrupts NF-kappa-B inhibitory function and results in increased IL-2 production. It is proposed that only a fraction of TNFAIP3 colocalized with TCR and CBM complex is cleaved, leaving the main TNFAIP3 pool intact.