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Gene Review

TNFAIP3  -  tumor necrosis factor, alpha-induced...

Homo sapiens

Synonyms: A20, OTU domain-containing protein 7C, OTUD7C, TNF alpha-induced protein 3, TNFA1P2, ...
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Disease relevance of TNFAIP3

  • Furthermore, cells stably expressing the active form of RIG-I induced an antiviral state that interfered with replication of vesicular stomatitis virus, an effect that was reversed by stable co-expression of A20 [1].
  • Cytokine induction of A20 mRNA in primary islets and insulinoma cells was rapid and observed within 1 h, consistent with A20 being an immediate early response gene in beta-cells [2].
  • Finally, expression of A20 could be induced at protein level by Sendai virus infection [3].
  • This effect is specific, as A20 does not block a noninducible, constitutively expressed reporter, Rous sarcoma virus-luciferase (RSV-LUC); nor does it block the c-Tat-inducible, NF-kappaB-independent reporter, human immunodeficiency virus-chloramphenicol acetyltransferase (HIV-CAT) [4].
  • A20 gene expression is regulated by TNF, Vitamin D and androgen in prostate cancer cells [5].
  • High A20 expression levels were observed in more aggressive breast tumors (ER-negative, progesterone receptor-negative and high histological grade) [6].
  • We also found evidence of two independent signals near TNFAIP3 associated with SLE, including one previously associated with rheumatoid arthritis (RA) [7].
  • We show that three independent SNPs in the TNFAIP3 region (rs13192841, rs2230926 and rs6922466) are associated with systemic lupus erythematosus (SLE) among individuals of European ancestry [8].

High impact information on TNFAIP3

  • It also induces binding of NEMO to the signaling inhibitor A20, and recruitment of A20 to the receptor [9].
  • The cytoprotective effect of A20 against apoptosis correlates with and is dependent on the abrogation of cytokine-induced NO production [10].
  • Stimulation of a B lymphoma cell line, A20, with intact anti-IgG antibody induced a direct, SH2-mediated association between Csk and a 62-kD phosphotyrosine-containing protein that was identified as RasGTPase-activating protein-associated p62 (GAP-A.p62) [11].
  • One of these is an A20 zinc finger that binds to a polar interaction interface of ubiquitin centered on Asp58 [12].
  • Recently, the underlying mechanism by which A20 downregulates NF-kappaB activation in response to the pro-inflammatory cytokine tumor necrosis factor (TNF) has been described [13].

Chemical compound and disease context of TNFAIP3


Biological context of TNFAIP3

  • The ability of A20 to block NF-kappaB activation was mapped to its C-terminal zinc finger domain [16].
  • Our findings suggest that ZNF216 and A20 have redundant and distinct roles in regulating NFkappaB activation and apoptosis [17].
  • Deletion of the N-terminal de-ubiquitination domain had no significant effect on the inhibitory effect of A20, whereas deletion or mutation of zinc finger motif 7 ablated the inhibitory function of A20 on IRF- or NF-kappaB-mediated gene expression [1].
  • We showed that PML inhibits A20 transactivation through the NF kappa B site by interfering with its binding to the promoter [18].
  • Expression of A20 completely blocked CARD domain containing DeltaRIG-I-induced IRF-3 Ser-396 phosphorylation, homodimerization, and DNA binding [1].

Anatomical context of TNFAIP3


Associations of TNFAIP3 with chemical compounds

  • Finally, A20 expression was sufficient to protect beta-cells from TNF-induced apoptosis [2].
  • We have previously identified in endothelial cells a gene product designated A20, that is rapidly and profoundly induced by tumor necrosis factor alpha (Dixit, V. M., Green, S., Sarma, V., Holzman, L. B., Wolf, F. W., O'Rourke, K., Ward, P. A., Prochownik, E. V., and Marks, R. M. (1990) J. Biol. Chem. 265, 2973-2978) [22].
  • Stimulation with LPS and PGN resulted in a significant increase in the level of A20 mRNA in primary cultured AECs and in NCI-H292 AECs [23].
  • A20 mRNA expression was down-regulated by 10nM calcitriol within 3-9h after treatment and up-regulated by androgen reaching maximal values by 6h after stimulation in LNCaP cells [5].
  • Enforced overexpression of either A1 or A20 inhibits LPS and cycloheximide-initiated apoptosis [24].

Physical interactions of TNFAIP3


Regulatory relationships of TNFAIP3

  • A20 also inhibited TNF and IL-1-induced NF-kappaB activation, suggesting that it may inhibit NF-kappaB activation signaled by diverse stimuli [16].
  • The promyelocytic leukemia protein represses A20-mediated transcription [18].
  • Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20 [1].
  • A20 inhibits NF-kappa B activation downstream of multiple Map3 kinases and interacts with the I kappa B signalosome [28].
  • ABIN-2 inhibits nuclear factor-kappaB (NF-kappaB) activity and is a possible effector of A20 regulation of NF-kappaB [29].

Other interactions of TNFAIP3

  • We also showed that stable overexpression of A20 inhibits apoptosis and caspase activation induced by PML/TNF alpha [18].
  • Domain mapping experiments indicated that the ZnF-A20 domain was responsible for interacting with IKKgamma and RIP, whereas the ZnF-AN1 domain interacted with TRAF6 [17].
  • Similarly, the NF-kappa B inducing activity of TAX, an activator of the I kappa B kinase complex, is also abrogated by A20 [28].
  • ZNF216 Is an A20-like and IkappaB kinase gamma-interacting inhibitor of NFkappaB activation [17].
  • These results suggest that A20 and ABIN-1 probably act independently of their mutual interaction [30].

Analytical, diagnostic and therapeutic context of TNFAIP3


  1. Negative regulation of the retinoic acid-inducible gene I-induced antiviral state by the ubiquitin-editing protein A20. Lin, R., Yang, L., Nakhaei, P., Sun, Q., Sharif-Askari, E., Julkunen, I., Hiscott, J. J. Biol. Chem. (2006) [Pubmed]
  2. Nuclear factor-kappaB regulates beta-cell death: a critical role for A20 in beta-cell protection. Liuwantara, D., Elliot, M., Smith, M.W., Yam, A.O., Walters, S.N., Marino, E., McShea, A., Grey, S.T. Diabetes (2006) [Pubmed]
  3. A20 is a potent inhibitor of TLR3- and Sendai virus-induced activation of NF-kappaB and ISRE and IFN-beta promoter. Wang, Y.Y., Li, L., Han, K.J., Zhai, Z., Shu, H.B. FEBS Lett. (2004) [Pubmed]
  4. A20 blocks endothelial cell activation through a NF-kappaB-dependent mechanism. Cooper, J.T., Stroka, D.M., Brostjan, C., Palmetshofer, A., Bach, F.H., Ferran, C. J. Biol. Chem. (1996) [Pubmed]
  5. A20 gene expression is regulated by TNF, Vitamin D and androgen in prostate cancer cells. Golovko, O., Nazarova, N., Tuohimaa, P. J. Steroid Biochem. Mol. Biol. (2005) [Pubmed]
  6. A20/TNFAIP3, a new estrogen-regulated gene that confers tamoxifen resistance in breast cancer cells. Vendrell, J.A., Ghayad, S., Ben-Larbi, S., Dumontet, C., Mechti, N., Cohen, P.A. Oncogene (2007) [Pubmed]
  7. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Graham, R.R., Cotsapas, C., Davies, L., Hackett, R., Lessard, C.J., Leon, J.M., Burtt, N.P., Guiducci, C., Parkin, M., Gates, C., Plenge, R.M., Behrens, T.W., Wither, J.E., Rioux, J.D., Fortin, P.R., Graham, D.C., Wong, A.K., Vyse, T.J., Daly, M.J., Altshuler, D., Moser, K.L., Gaffney, P.M. Nat. Genet. (2008) [Pubmed]
  8. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Musone, S.L., Taylor, K.E., Lu, T.T., Nititham, J., Ferreira, R.C., Ortmann, W., Shifrin, N., Petri, M.A., Kamboh, M.I., Manzi, S., Seldin, M.F., Gregersen, P.K., Behrens, T.W., Ma, A., Kwok, P.Y., Criswell, L.A. Nat. Genet. (2008) [Pubmed]
  9. Recruitment of the IKK signalosome to the p55 TNF receptor: RIP and A20 bind to NEMO (IKKgamma) upon receptor stimulation. Zhang, S.Q., Kovalenko, A., Cantarella, G., Wallach, D. Immunity (2000) [Pubmed]
  10. A20 inhibits cytokine-induced apoptosis and nuclear factor kappaB-dependent gene activation in islets. Grey, S.T., Arvelo, M.B., Hasenkamp, W., Bach, F.H., Ferran, C. J. Exp. Med. (1999) [Pubmed]
  11. Differential effects of B cell receptor and B cell receptor-FcgammaRIIB1 engagement on docking of Csk to GTPase-activating protein (GAP)-associated p62. Vuica, M., Desiderio, S., Schneck, J.P. J. Exp. Med. (1997) [Pubmed]
  12. A new side to ubiquitin. Raiborg, C., Slagsvold, T., Stenmark, H. Trends Biochem. Sci. (2006) [Pubmed]
  13. A20 inhibits NF-kappaB activation by dual ubiquitin-editing functions. Heyninck, K., Beyaert, R. Trends Biochem. Sci. (2005) [Pubmed]
  14. Identification of a novel mechanism of NF-kappaB inactivation by progesterone through progesterone receptors in Hec50co poorly differentiated endometrial cancer cells: induction of A20 and ABIN-2. Davies, S., Dai, D., Feldman, I., Pickett, G., Leslie, K.K. Gynecol. Oncol. (2004) [Pubmed]
  15. The effects of different doses of atorvastatin on plasma endothelin-1 levels in type 2 diabetic patients with dyslipidemia. Lam, H.C., Chu, C.H., Wei, M.C., Keng, H.M., Lu, C.C., Sun, C.C., Lee, J.K., Chuang, M.J., Wang, M.C., Tai, M.H. Exp. Biol. Med. (Maywood) (2006) [Pubmed]
  16. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Song, H.Y., Rothe, M., Goeddel, D.V. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  17. ZNF216 Is an A20-like and IkappaB kinase gamma-interacting inhibitor of NFkappaB activation. Huang, J., Teng, L., Li, L., Liu, T., Li, L., Chen, D., Xu, L.G., Zhai, Z., Shu, H.B. J. Biol. Chem. (2004) [Pubmed]
  18. The promyelocytic leukemia protein represses A20-mediated transcription. Wu, W.S., Xu, Z.X., Chang, K.S. J. Biol. Chem. (2002) [Pubmed]
  19. A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation. Daniel, S., Arvelo, M.B., Patel, V.I., Longo, C.R., Shrikhande, G., Shukri, T., Mahiou, J., Sun, D.W., Mottley, C., Grey, S.T., Ferran, C. Blood (2004) [Pubmed]
  20. Combined expression of A1 and A20 achieves optimal protection of renal proximal tubular epithelial cells. Kunter, U., Daniel, S., Arvelo, M.B., Choi, J., Shukri, T., Patel, V.I., Longo, C.R., Scali, S.T., Shrikhande, G., Rocha, E., Czismadia, E., Mottley, C., Grey, S.T., Floege, J., Ferran, C. Kidney Int. (2005) [Pubmed]
  21. Tag Polymorphisms at the A20 (TNFAIP3) Locus Are Associated With Lower Gene Expression and Increased Risk of Coronary Artery Disease in Type 2 Diabetes. Boonyasrisawat, W., Eberle, D., Bacci, S., Zhang, Y.Y., Nolan, D., Gervino, E.V., Johnstone, M.T., Trischitta, V., Shoelson, S.E., Doria, A. Diabetes (2007) [Pubmed]
  22. The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type of zinc finger protein. Opipari, A.W., Boguski, M.S., Dixit, V.M. J. Biol. Chem. (1990) [Pubmed]
  23. A20 inhibits toll-like receptor 2- and 4-mediated interleukin-8 synthesis in airway epithelial cells. Gon, Y., Asai, Y., Hashimoto, S., Mizumura, K., Jibiki, I., Machino, T., Ra, C., Horie, T. Am. J. Respir. Cell Mol. Biol. (2004) [Pubmed]
  24. Lipopolysaccharide induces the antiapoptotic molecules, A1 and A20, in microvascular endothelial cells. Hu, X., Yee, E., Harlan, J.M., Wong, F., Karsan, A. Blood (1998) [Pubmed]
  25. A20 zinc finger protein inhibits TNF-induced apoptosis and stress response early in the signaling cascades and independently of binding to TRAF2 or 14-3-3 proteins. Lademann, U., Kallunki, T., Jäättelä, M. Cell Death Differ. (2001) [Pubmed]
  26. The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6. Heyninck, K., Beyaert, R. FEBS Lett. (1999) [Pubmed]
  27. A20 zinc finger protein inhibits TNF and IL-1 signaling. Jäättelä, M., Mouritzen, H., Elling, F., Bastholm, L. J. Immunol. (1996) [Pubmed]
  28. A20 inhibits NF-kappa B activation downstream of multiple Map3 kinases and interacts with the I kappa B signalosome. Zetoune, F.S., Murthy, A.R., Shao, Z., Hlaing, T., Zeidler, M.G., Li, Y., Vincenz, C. Cytokine (2001) [Pubmed]
  29. ABIN-2 protects endothelial cells from death and has a role in the antiapoptotic effect of angiopoietin-1. Tadros, A., Hughes, D.P., Dunmore, B.J., Brindle, N.P. Blood (2003) [Pubmed]
  30. Structure-function analysis of the A20-binding inhibitor of NF-kappa B activation, ABIN-1. Heyninck, K., Kreike, M.M., Beyaert, R. FEBS Lett. (2003) [Pubmed]
  31. Genetic engineering of a suboptimal islet graft with A20 preserves beta cell mass and function. Grey, S.T., Longo, C., Shukri, T., Patel, V.I., Csizmadia, E., Daniel, S., Arvelo, M.B., Tchipashvili, V., Ferran, C. J. Immunol. (2003) [Pubmed]
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