TNFAIP3

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, AIFBL1
External IDs	OMIM: 191163; MGI: 1196377; HomoloGene: 4582; GeneCards: TNFAIP3; OMA:TNFAIP3 - orthologs
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 18,876,658 bp [2] End 18,891,405 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in vena cava mucosa of paranasal sinus appendix epithelium of nasopharynx pericardium mucosa of urinary bladder skin of thigh thymus lymph node cartilage tissue Top expressed in neural layer of retina retinal pigment epithelium mesenteric lymph nodes thymus epithelium of lens granulocyte Paneth cell jejunum left colon stroma of bone marrow More reference expression data BioGPS 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 protein binding catalytic activity thiol-dependent deubiquitinase hydrolase activity identical protein binding Lys63-specific deubiquitinase activity transferase activity Cellular component cytoplasm cytosol lysosome extracellular exosome 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 complex 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 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: 18.88 – 18.89 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/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

• 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. 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. 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. 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. 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. 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. 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

• 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

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