TNFAIP3

Tumor necrosis factor, alpha-induced protein 3
Rendering based on PDB 2EQE​.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2EQE​, 2EQF​, 2EQG​, 2VFJ​, 3DKB​, 3OJ3​, 3OJ4​, 3VUW​, 3VUX​, 3VUY​, 3ZJD​, 3ZJE​, 3ZJF​, 3ZJG​
Identifiers
Symbols	TNFAIP3 ; A20; OTUD7C; TNFA1P2
External IDs	OMIM: 191163 MGI: 1196377 HomoloGene: 4582 GeneCards: TNFAIP3 Gene
EC number	3.4.19.12
Gene ontology Molecular function • protease binding • DNA binding • ubiquitin-protein transferase activity • ubiquitin-specific protease activity • protein binding • zinc ion binding • ligase activity • kinase binding • ubiquitin binding • protein self-association • K63-linked polyubiquitin binding Cellular component • nucleus • cytoplasm • lysosome • centrosome • cytosol • extracellular exosome Biological process • B-1 B cell homeostasis • response to molecule of bacterial origin • regulation of germinal center formation • negative regulation of chronic inflammatory response • apoptotic process • inflammatory response • protein deubiquitination • negative regulation of protein ubiquitination • negative regulation of NF-kappaB transcription factor activity • negative regulation of type I interferon production • response to muramyl dipeptide • negative regulation of interleukin-1 beta production • negative regulation of interleukin-2 production • negative regulation of interleukin-6 production • negative regulation of tumor necrosis factor production • negative regulation of toll-like receptor 2 signaling pathway • negative regulation of toll-like receptor 3 signaling pathway • negative regulation of toll-like receptor 4 signaling pathway • negative regulation of toll-like receptor 5 signaling pathway • protein K11-linked deubiquitination • nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway • negative regulation of I-kappaB kinase/NF-kappaB signaling • innate immune response • positive regulation of protein catabolic process • negative regulation of cyclin-dependent protein serine/threonine kinase activity • negative regulation of bone resorption • negative regulation of innate immune response • negative regulation of smooth muscle cell proliferation • regulation of defense response to virus by host • regulation of inflammatory response • negative regulation of inflammatory response • negative regulation of B cell activation • protein oligomerization • regulation of vascular wound healing • cellular response to hydrogen peroxide • nucleotide-binding oligomerization domain containing signaling pathway • negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway • negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway • protein K63-linked deubiquitination • protein K48-linked ubiquitination • protein K48-linked deubiquitination • cellular response to lipopolysaccharide • protein deubiquitination involved in ubiquitin-dependent protein catabolic process • tolerance induction to lipopolysaccharide • establishment of protein localization to vacuole • negative regulation of osteoclast proliferation • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors • positive regulation of cellular protein catabolic process • positive regulation of hepatocyte proliferation • negative regulation of CD40 signaling pathway • negative regulation of endothelial cell apoptotic process Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7128	21929
Ensembl	ENSG00000118503	ENSMUSG00000019850
UniProt	P21580	Q60769
RefSeq (mRNA)	NM_001270507	NM_001166402
RefSeq (protein)	NP_001257436	NP_001159874
Location (UCSC)	Chr 6: 137.87 – 137.88 Mb	Chr 10: 19 – 19.02 Mb
PubMed search

Tumor necrosis factor, alpha-induced protein 3 is a protein that in humans is encoded by the TNFAIP3 gene.^[1][2]

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 has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. Knockout studies of a similar gene in mice suggested that this gene is critical for limiting inflammation by terminating TNF-induced NF-kappa B responses.^[2]

Interactions

TNFAIP3 has been shown to interact with TNIP1,^[3] TRAF1,^[4][5] TRAF2,^[4] IKBKG,^[6] TAX1BP1,^[7] YWHAB,^[8] YWHAZ,^[8][9] TRAF6^[5][10] and YWHAH.^[8][9]

Association with rheumatoid arthritis

The TNFAIP3 locus is implicated as a positively associated factor in rheumatoid arthritis (RA). The rs5029937 (T) and the rs6920220 (A) SNPs increase risk of RA by 20 to 40% respectively.^[11] A third SNP, rs10499194 (T) is found less often in rheumatoid arthritis but this negative association may not be statistically meaningful.

References

1. Opipari AW Jr, Boguski MS, Dixit VM (October 1990). "The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type of zinc finger protein". J Biol Chem 265 (25): 14705–8. PMID 2118515.
2. "Entrez Gene: TNFAIP3 tumor necrosis factor, alpha-induced protein 3".
3. Heyninck, K; De Valck D; Vanden Berghe W; Van Criekinge W; Contreras R; Fiers W; Haegeman G; Beyaert R (June 1999). "The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN". J. Cell Biol. (UNITED STATES) 145 (7): 1471–82. doi:10.1083/jcb.145.7.1471. ISSN 0021-9525. PMC 2133159. PMID 10385526.
4. Song, H Y; Rothe M; Goeddel D V (June 1996). "The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 93 (13): 6721–5. doi:10.1073/pnas.93.13.6721. ISSN 0027-8424. PMC 39093. PMID 8692885.
5. Heyninck, K; Beyaert R (January 1999). "The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6". FEBS Lett. (NETHERLANDS) 442 (2–3): 147–50. doi:10.1016/S0014-5793(98)01645-7. ISSN 0014-5793. PMID 9928991.
6. Zhang, S Q; Kovalenko A; Cantarella G; Wallach D (March 2000). "Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation". Immunity (UNITED STATES) 12 (3): 301–11. doi:10.1016/S1074-7613(00)80183-1. ISSN 1074-7613. PMID 10755617.
7. De Valck, D; Jin D Y; Heyninck K; Van de Craen M; Contreras R; Fiers W; Jeang K T; Beyaert R (July 1999). "The zinc finger protein A20 interacts with a novel anti-apoptotic protein which is cleaved by specific caspases". Oncogene (ENGLAND) 18 (29): 4182–90. doi:10.1038/sj.onc.1202787. ISSN 0950-9232. PMID 10435631.
8. Vincenz, C; Dixit V M (August 1996). "14-3-3 proteins associate with A20 in an isoform-specific manner and function both as chaperone and adapter molecules". J. Biol. Chem. (UNITED STATES) 271 (33): 20029–34. doi:10.1074/jbc.271.33.20029. ISSN 0021-9258. PMID 8702721.
9. De Valck, D; Heyninck K; Van Criekinge W; Vandenabeele P; Fiers W; Beyaert R (September 1997). "A20 inhibits NF-kappaB activation independently of binding to 14-3-3 proteins". Biochem. Biophys. Res. Commun. (UNITED STATES) 238 (2): 590–4. doi:10.1006/bbrc.1997.7343. ISSN 0006-291X. PMID 9299557.
10. Evans, P C; Taylor E R; Coadwell J; Heyninck K; Beyaert R; Kilshaw P J (August 2001). "Isolation and characterization of two novel A20-like proteins". Biochem. J. (England) 357 (Pt 3): 617–23. doi:10.1042/0264-6021:3570617. ISSN 0264-6021. PMC 1221992. PMID 11463333.
11. Stahl EA, Raychaudhuri S, Remmers EF, et al. (June 2010). "Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci". Nat. Genet. 42 (6): 508–14. doi:10.1038/ng.582. PMID 20453842.

Further reading

• Dixit VM, Green S, Sarma V, et al. (1990). "Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin". J. Biol. Chem. 265 (5): 2973–8. PMID 2406243.
• Cooper JT, Stroka DM, Brostjan C, et al. (1996). "A20 blocks endothelial cell activation through a NF-kappaB-dependent mechanism". J. Biol. Chem. 271 (30): 18068–73. doi:10.1074/jbc.271.30.18068. PMID 8663499.
• Song HY, Rothe M, Goeddel DV (1996). "The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation". Proc. Natl. Acad. Sci. U.S.A. 93 (13): 6721–5. doi:10.1073/pnas.93.13.6721. PMC 39093. PMID 8692885.
• Vincenz C, Dixit VM (1996). "14-3-3 proteins associate with A20 in an isoform-specific manner and function both as chaperone and adapter molecules". J. Biol. Chem. 271 (33): 20029–34. doi:10.1074/jbc.271.33.20029. PMID 8702721.
• De Valck D, Heyninck K, Van Criekinge W, et al. (1996). "A20, an inhibitor of cell death, self-associates by its zinc finger domain". FEBS Lett. 384 (1): 61–4. doi:10.1016/0014-5793(96)00283-9. PMID 8797804.
• De Valck D, Heyninck K, Van Criekinge W, et al. (1997). "A20 inhibits NF-kappaB activation independently of binding to 14-3-3 proteins". Biochem. Biophys. Res. Commun. 238 (2): 590–4. doi:10.1006/bbrc.1997.7343. PMID 9299557.
• Eliopoulos AG, Blake SM, Floettmann JE, et al. (1999). "Epstein-Barr virus-encoded latent membrane protein 1 activates the JNK pathway through its extreme C terminus via a mechanism involving TRADD and TRAF2". J. Virol. 73 (2): 1023–35. PMC 103922. PMID 9882303.
• Heyninck K, Beyaert R (1999). "The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6". FEBS Lett. 442 (2–3): 147–50. doi:10.1016/S0014-5793(98)01645-7. PMID 9928991.
• Heyninck K, De Valck D, Vanden Berghe W, et al. (1999). "The zinc finger protein A20 inhibits TNF-induced NF-kappaB-dependent gene expression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappaB-inhibiting protein ABIN". J. Cell Biol. 145 (7): 1471–82. doi:10.1083/jcb.145.7.1471. PMC 2133159. PMID 10385526.
• De Valck D, Jin DY, Heyninck K, et al. (1999). "The zinc finger protein A20 interacts with a novel anti-apoptotic protein which is cleaved by specific caspases". Oncogene 18 (29): 4182–90. doi:10.1038/sj.onc.1202787. PMID 10435631.
• Zhang SQ, Kovalenko A, Cantarella G, Wallach D (2000). "Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation". Immunity 12 (3): 301–11. doi:10.1016/S1074-7613(00)80183-1. PMID 10755617.
• Lee EG, Boone DL, Chai S, et al. (2000). "Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice". Science 289 (5488): 2350–4. doi:10.1126/science.289.5488.2350. PMC 3582399. PMID 11009421.
• Klinkenberg M, Van Huffel S, Heyninck K, Beyaert R (2001). "Functional redundancy of the zinc fingers of A20 for inhibition of NF-kappaB activation and protein-protein interactions". FEBS Lett. 498 (1): 93–7. doi:10.1016/S0014-5793(01)02504-2. PMID 11389905.
• Van Huffel S, Delaei F, Heyninck K, et al. (2001). "Identification of a novel A20-binding inhibitor of nuclear factor-kappa B activation termed ABIN-2". J. Biol. Chem. 276 (32): 30216–23. doi:10.1074/jbc.M100048200. PMID 11390377.
• Evans PC, Taylor ER, Coadwell J, et al. (2001). "Isolation and characterization of two novel A20-like proteins". Biochem. J. 357 (Pt 3): 617–23. doi:10.1042/0264-6021:3570617. PMC 1221992. PMID 11463333.
• Baltathakis I, Alcantara O, Boldt DH (2001). "Expression of different NF-kappaB pathway genes in dendritic cells (DCs) or macrophages assessed by gene expression profiling". J. Cell. Biochem. 83 (2): 281–90. doi:10.1002/jcb.1231. PMID 11573245.
• Zetoune FS, Murthy AR, Shao Z, et al. (2002). "A20 inhibits NF-kappa B activation downstream of multiple Map3 kinases and interacts with the I kappa B signalosome". Cytokine 15 (6): 282–98. doi:10.1006/cyto.2001.0921. PMID 11594795.
• Wu WS, Xu ZX, Chang KS (2002). "The promyelocytic leukemia protein represses A20-mediated transcription". J. Biol. Chem. 277 (35): 31734–9. doi:10.1074/jbc.M201648200. PMID 12080044.
• He KL, Ting AT (2002). "A20 inhibits tumor necrosis factor (TNF) alpha-induced apoptosis by disrupting recruitment of TRADD and RIP to the TNF receptor 1 complex in Jurkat T cells". Mol. Cell. Biol. 22 (17): 6034–45. doi:10.1128/MCB.22.17.6034-6045.2002. PMC 133997. PMID 12167698.