Protein-coding gene in the species Homo sapiens
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, AIFBL1External IDs OMIM : 191163 MGI : 1196377 HomoloGene : 4582 GeneCards : TNFAIP3 Wikidata
Tumor necrosis factor, alpha-induced protein 3 or A20 is a protein that in humans is encoded by the TNFAIP3 gene .[5] [6]
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] [10] 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 .[9]
Interactions [ edit ]
TNFAIP3 has been shown to interact with TNIP1 ,[11] TRAF1 ,[12] [13] TRAF2 ,[12] IKBKG ,[14] TAX1BP1 ,[15] YWHAB ,[16] YWHAZ ,[16] [17] TRAF6 [13] [18] and YWHAH .[16] [17]
Association with rheumatoid arthritis [ edit ]
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.[19] A third SNP, rs10499194 (T) is found less often in rheumatoid arthritis but this negative association may not be statistically meaningful.
Other diseases [ edit ]
An association with infantile onset intractable inflammatory bowel disease has also been reported.[20]
See also [ edit ]
References [ edit ]
^ a b c GRCh38: Ensembl release 89: ENSG00000118503 – Ensembl , May 2017
^ a b c GRCm38: Ensembl release 89: ENSMUSG00000019850 – Ensembl , May 2017
^ "Human PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^ "Mouse PubMed Reference:" . National Center for Biotechnology Information, U.S. National Library of Medicine .
^ 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. doi :10.1016/S0021-9258(18)77165-2 . PMID 2118515 .
^ "Entrez Gene: TNFAIP3 tumor necrosis factor, alpha-induced protein 3" .
^ 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 .
^ Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, Ma A (September 2000). "Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice" . Science . 289 (5488): 2350–2354. Bibcode :2000Sci...289.2350L . doi :10.1126/science.289.5488.2350 . PMC 3582399 . PMID 11009421 .
^ a b 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): 60. doi :10.1038/s41420-018-0056-3 . PMC 5955943 . PMID 29796309 .
^ 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 .
^ 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 . 145 (7). UNITED STATES: 1471–82. doi :10.1083/jcb.145.7.1471 . ISSN 0021-9525 . PMC 2133159 . PMID 10385526 .
^ a b 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. 93 (13). UNITED STATES: 6721–5. Bibcode :1996PNAS...93.6721S . doi :10.1073/pnas.93.13.6721 . ISSN 0027-8424 . PMC 39093 . PMID 8692885 .
^ a b 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 . 442 (2–3). NETHERLANDS: 147–50. doi :10.1016/S0014-5793(98)01645-7 . ISSN 0014-5793 . PMID 9928991 . S2CID 19072203 .
^ 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 . 12 (3). UNITED STATES: 301–11. doi :10.1016/S1074-7613(00)80183-1 . ISSN 1074-7613 . PMID 10755617 .
^ 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 . 18 (29). ENGLAND: 4182–90. doi :10.1038/sj.onc.1202787 . ISSN 0950-9232 . PMID 10435631 .
^ a b c 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 . 271 (33). UNITED STATES: 20029–34. doi :10.1074/jbc.271.33.20029 . ISSN 0021-9258 . PMID 8702721 .
^ a b 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 . 238 (2). UNITED STATES: 590–4. doi :10.1006/bbrc.1997.7343 . ISSN 0006-291X . PMID 9299557 .
^ 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 . 357 (Pt 3). England: 617–23. doi :10.1042/0264-6021:3570617 . ISSN 0264-6021 . PMC 1221992 . PMID 11463333 .
^ 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 .
^ 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 [ edit ]
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. doi :10.1016/S0021-9258(19)39896-5 . 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): 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 [ edit ]
Overview of all the structural information available in the PDB for UniProt : P21580 (Tumor necrosis factor alpha-induced protein 3) at the PDBe-KB .