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Protein TNFAIP3 PDB 2EQE.png
Available structures
PDBOrtholog search: PDBe RCSB
AliasesTNFAIP3, A20, OTUD7C, TNFA1P2, AISBL, TNF alpha induced protein 3
External IDsOMIM: 191163 MGI: 1196377 HomoloGene: 4582 GeneCards: TNFAIP3
Gene location (Human)
Chromosome 6 (human)
Chr.Chromosome 6 (human)[1]
Chromosome 6 (human)
Genomic location for TNFAIP3
Genomic location for TNFAIP3
Band6q23.3Start137,867,214 bp[1]
End137,883,312 bp[1]
RNA expression pattern
PBB GE TNFAIP3 202644 s at fs.png

PBB GE TNFAIP3 202643 s at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 6: 137.87 – 137.88 MbChr 10: 19 – 19.02 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

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 homolog proteins 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]


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[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.[18] 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.[19]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000118503 - Ensembl, May 2017
  2. ^ a b c 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. ^ 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). doi:10.1038/s41420-018-0056-3. PMC 5955943.
  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. ^ 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. 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. ^ 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. NETHERLANDS. 442 (2–3): 147–50. doi:10.1016/S0014-5793(98)01645-7. ISSN 0014-5793. PMID 9928991.
  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. ^ 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. UNITED STATES. 271 (33): 20029–34. doi:10.1074/jbc.271.33.20029. ISSN 0021-9258. PMID 8702721.
  16. ^ 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. 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[edit]