TNFAIP3

Tumor necrosis factor, alpha-induced protein 3 or A20 is a protein that in humans is encoded by the TNFAIP3 gene.[5][6]

TNFAIP3
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2EQF, 2EQG, 2VFJ, 3DKB, 3OJ3, 3OJ4, 3VUW, 3VUX, 3VUY, 3ZJD, 3ZJE, 3ZJF, 3ZJG, 4ZRH, 4ZS5
Identifiers
Aliases	TNFAIP3, A20, OTUD7C, TNFA1P2, AISBL, TNF alpha induced protein 3
External IDs	OMIM: 191163 MGI: 1196377 HomoloGene: 4582 GeneCards: TNFAIP3
Gene location (Human) Chr. Chromosome 6 (human)[1] Band 6q23.3 Start 137,867,214 bp[1] End 137,883,312 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 A3|10 8.08 cM Start 19,000,910 bp[2] End 19,015,657 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • DNA binding • cysteine-type peptidase activity • zinc ion binding • metal ion binding • ubiquitin-protein transferase activity • protease binding • protein self-association • peptidase activity • ligase activity • kinase binding • K63-linked polyubiquitin modification-dependent protein binding • ubiquitin binding • GO:0001948 protein binding • catalytic activity • thiol-dependent ubiquitin-specific protease activity • hydrolase activity • identical protein binding • Lys63-specific deubiquitinase activity • transferase activity Cellular component • cytoplasm • cytosol • lysosome • extracellular exosome • cell nucleus • intracellular membrane-bounded organelle Biological process • regulation of germinal center formation • positive regulation of hepatocyte proliferation • negative regulation of endothelial cell apoptotic process • negative regulation of interleukin-1 beta production • negative regulation of smooth muscle cell proliferation • regulation of vascular wound healing • B-1 B cell homeostasis • protein K48-linked deubiquitination • positive regulation of protein catabolic process • negative regulation of cyclin-dependent protein serine/threonine kinase activity • regulation of defense response to virus by host • protein deubiquitination involved in ubiquitin-dependent protein catabolic process • negative regulation of toll-like receptor 2 signaling pathway • negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway • regulation of tumor necrosis factor-mediated signaling pathway • negative regulation of interleukin-6 production • negative regulation of B cell activation • negative regulation of toll-like receptor 5 signaling pathway • tolerance induction to lipopolysaccharide • response to muramyl dipeptide • negative regulation of chronic inflammatory response • negative regulation of cell death • negative regulation of I-kappaB kinase/NF-kappaB signaling • proteolysis • establishment of protein localization to vacuole • protein deubiquitination • negative regulation of protein ubiquitination • protein K48-linked ubiquitination • protein K63-linked deubiquitination • negative regulation of CD40 signaling pathway • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors • protein oligomerization • protein K11-linked deubiquitination • regulation of inflammatory response • negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway • negative regulation of innate immune response • negative regulation of osteoclast proliferation • negative regulation of tumor necrosis factor production • negative regulation of type I interferon production • metabolism • inflammatory response • response to molecule of bacterial origin • negative regulation of NF-kappaB transcription factor activity • negative regulation of interleukin-2 production • negative regulation of inflammatory response • negative regulation of toll-like receptor 3 signaling pathway • nucleotide-binding oligomerization domain containing signaling pathway • cellular response to lipopolysaccharide • negative regulation of toll-like receptor 4 signaling pathway • negative regulation of bone resorption • cellular response to hydrogen peroxide • apoptotic process • protein ubiquitination • cytoskeleton organization • cell migration • positive regulation of Wnt signaling pathway • protein K29-linked deubiquitination • positive regulation of cellular protein catabolic process • protein K33-linked deubiquitination Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7128	21929
Ensembl	ENSG00000118503	ENSMUSG00000019850
UniProt	P21580	Q60769
RefSeq (mRNA)	NM_001270507 NM_001270508 NM_006290	NM_001166402 NM_009397
RefSeq (protein)	NP_001257436 NP_001257437 NP_006281	NP_001159874 NP_033423
Location (UCSC)	Chr 6: 137.87 – 137.88 Mb	Chr 10: 19 – 19.02 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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 a deubiquitinating enzyme, and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. The A20 protein is ancient, and protein homolog can be found as far back as cnidaria (corals, jellyfish, anemones) with a conserved protein domain composition. [7] Using knockout mouse models of TNFAIP3 and its transcriptional repressor (i.e. KCHIP3), TNFAIP3 has been shown to be critical for limiting inflammation by terminating endotoxin- and TNF-induced NF-kappa B responses.[8][9] In brief, deubiquitinase function of TNFAIP3 was shown to remove ubiquitin chains from VE-cadherin to prevent loss of VE-cadherin at the endothelial adherens junctions. [8]

Interactions

TNFAIP3 has been shown to interact with TNIP1,[10] TRAF1,[11][12] TRAF2,[11] IKBKG,[13] TAX1BP1,[14] YWHAB,[15] YWHAZ,[15][16] TRAF6[12][17] and YWHAH.[15][16]

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.[18] A third SNP, rs10499194 (T) is found less often in rheumatoid arthritis but this negative association may not be statistically meaningful.

Other diseases

An association with infantile onset intractable inflammatory bowel disease has also been reported.[19]

See also

• Haploinsufficiency of A20

References

1. GRCh38: Ensembl release 89: ENSG00000118503 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000019850 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. 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.
6. "Entrez Gene: TNFAIP3 tumor necrosis factor, alpha-induced protein 3".
7. Staal J, Driege Y, Haegman M, Borghi A, Hulpiau P, Lievens L, et al. (2018). "Ancient Origin of the CARD-Coiled Coil/Bcl10/MALT1-Like Paracaspase Signaling Complex Indicates Unknown Critical Functions". Frontiers in Immunology. 9: 1136. doi:10.3389/fimmu.2018.01136. PMC 5978004. PMID 29881386.
8. Soni D, Wang DM, Regmi SC, Mittal M, Vogel SM, Schlüter D, Tiruppathi C (May 2018). "Deubiquitinase function of A20 maintains and repairs endothelial barrier after lung vascular injury". Cell Death Discovery. 4 (60). doi:10.1038/s41420-018-0056-3. PMC 5955943. PMID 29796309.
9. Tiruppathi C, Soni D, Wang DM, et al. (March 2014). "The transcription factor DREAM represses A20 and mediates inflammation". Nat Immunol. 15 (3): 239–247. doi:10.1038/ni.2823. PMC 4005385. PMID 24487321.
10. 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.
11. 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. Bibcode:1996PNAS...93.6721S. doi:10.1073/pnas.93.13.6721. ISSN 0027-8424. PMC 39093. PMID 8692885.
12. 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. S2CID 19072203.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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. PMC 4243840. PMID 20453842.
19. Zheng C, Huang Y, Ye Z, Wang Y, Tang Z, Lu J, Wu J, Zhou Y, Wang L, Huang Z, Yang H, Xue A (2018) Infantile onset intractable inflammatory bowel disease due to novel heterozygous mutations in TNFAIP3 (A20). Inflamm Bowel Dis doi: 10.1093/ibd/izy165

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.
• Meng Z, Zhao T, Zhou K, et al. (2017). "A20 Ameliorates Intracerebral Hemorrhage-Induced Inflammatory Injury by Regulating TRAF6 Polyubiquitination". J. Immunol. 198 (2): 820–31. doi:10.4049/jimmunol.1600334. PMC 5220121. PMID 27986908.
• 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. Bibcode:1996PNAS...93.6721S. 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. S2CID 29040964.
• 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. doi:10.1128/JVI.73.2.1023-1035.1999. 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. S2CID 19072203.
• 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. hdl:1854/LU-113881. 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. Bibcode:2000Sci...289.2350L. 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. S2CID 32414520.
• 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. S2CID 12756967.
• 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.
• Soni D, Wang DM, Regmi SC, Mittal M, Vogel SM, Schlüter D, Tiruppathi C (May 2018). "Deubiquitinase function of A20 maintains and repairs endothelial barrier after lung vascular injury". Cell Death Discovery. 4 (60). doi:10.1038/s41420-018-0056-3. PMC 5955943. PMID 29796309.
• 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.

External links

• Overview of all the structural information available in the PDB for UniProt: P21580 (Tumor necrosis factor alpha-induced protein 3) at the PDBe-KB.