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MGP003160

UniProt Annotations

Entry Information
Gene Nametumor necrosis factor, alpha-induced protein 3
Protein EntryTNAP3_HUMAN
UniProt IDP21580
SpeciesHuman
Comments
Comment typeDescription
Catalytic ActivityThiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C- terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal). {ECO:0000269|PubMed:17961127, ECO:0000269|PubMed:18164316, ECO:0000269|PubMed:23827681}.
DomainThe A20-type zinc fingers mediate the ubiquitin ligase activity. The A20-type zinc finger 4 selectively recognizes 'Lys- 63'-linked polyubiquitin. The A20-type zinc finger 4-7 are sufficient to bind polyubiquitin. {ECO:0000269|PubMed:15258597}.
DomainThe OTU domain mediates the deubiquitinase activity. {ECO:0000269|PubMed:15258597}.
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}.
InductionBy TNF.
InteractionQ9Y6K9:IKBKG; NbExp=4; IntAct=EBI-527670, EBI-81279; Q9Y3C5:RNF11; NbExp=2; IntAct=EBI-527670, EBI-396669; P68510:Ywhah (xeno); NbExp=3; IntAct=EBI-527670, EBI-444641;
PtmProteolytically 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. {ECO:0000269|PubMed:18223652, ECO:0000269|PubMed:20804738}.
SimilarityBelongs to the peptidase C64 family. {ECO:0000305}.
SimilarityContains 1 OTU domain. {ECO:0000255|PROSITE- ProRule:PRU00139}.
SimilarityContains 7 A20-type zinc fingers. {ECO:0000255|PROSITE-ProRule:PRU00451}.
Subcellular LocationA20p50: Cytoplasm.
Subcellular LocationCytoplasm. Nucleus. Lysosome.
SubunitHomodimer. Interacts with TNIP1, TAX1BP1 and TRAF2. Interacts with RNF11, ITCH and TAX1BP1 only after TNF stimulation; these interaction are transient and they are lost after 1 hour of stimulation with TNF (By similarity). Interacts with YWHAZ and YWHAH. Interacts with IKBKG; the interaction is induced by TNF stimulation and by polyubiquitin. Interacts with RIPK1. Interacts with UBE2N; the interaction requires TAX1BP1. Interacts with TRAF6; the interaction is inhibited by HTLV-1 protein Tax. {ECO:0000250, ECO:0000269|PubMed:10435631, ECO:0000269|PubMed:16684768, ECO:0000269|PubMed:19131965, ECO:0000269|PubMed:21095585, ECO:0000269|PubMed:22099304, ECO:0000269|PubMed:8692885, ECO:0000269|PubMed:9299557, ECO:0000269|PubMed:9882303}.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/TNFAIP3ID42600ch6q23.html";
Web ResourceName=SeattleSNPs; URL="http://pga.gs.washington.edu/data/tnfaip3/";
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