TNFAIP3

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TNFAIP3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTNFAIP3, A20, OTUD7C, TNFA1P2, AISBL, TNF alpha induced protein 3, AIFBL1
External IDsOMIM: 191163 MGI: 1196377 HomoloGene: 4582 GeneCards: TNFAIP3
Orthologs
SpeciesHumanMouse
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 MbChr 10: 18.88 – 18.89 Mb
PubMed search[3][4]
Wikidata
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 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

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

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

An association with infantile onset intractable inflammatory bowel disease has also been reported.[20]

See also

References

  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. doi:10.1016/S0021-9258(18)77165-2. 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. ^ 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.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ 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

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.


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