A20, TNFalpha-induced protein 3, TNFAIP3 (theoretical molecular weight 95 kDa) is an important regulator of pro-inflammatory signaling pathways such as NF-kB activation and tumor necrosis factor (TNF)-mediated programmed cell death (1, 2). In macrophages, A20/TNFAIP3 controls the release of IL-1 beta/IL-18 by regulating NLRP3 inflammasome activity and CXCL9/CXCL10 production via STAT1 signaling. By regulating the expression of inflammatory molecules such as IL-6 and anti-apoptotic proteins in dendritic cells, A20/TNFAIP3 maintains T-cell and B-cell homeostasis.
A20/TNFAIP3 is a highly conserved protein sharing >90% amino acid sequence identity across various mammalian species and is highly expressed in T-cell and B-cells. Coding and non-coding single nucleotide polymorphisms (SNPs) of A20/TNFAIP3 have been associated with multiple autoinflammatory and autoimmune diseases including type 1 diabetes, rheumatoid arthritis, Crohn's disease, and systemic lupus erythematosus (SLE) (3). The two domains of A20/TNFAIP3 cooperate to regulate NF-kB signaling. Its N-terminal ovarian tumor (OTU) domain contains a catalytic cysteine (C103) which functions as a K63 deubiquitinase, whereas the 7 zinc fingers that make up the C-terminal domain mediate K48 polyubiquitination. To regulate NF-kB signaling, A20/TNFAIP3 removes K63-polyubiquitin chains from receptor-interacting protein 1 (RIP1) and NF-kB essential modulator (NEMO), thus preventing interactions with downstream partners. A20/TNFAIP3 also contributes to the degradation of RIP1 and Ubc13 through the addition of K48 polyubiquitin chains (4).
1.Dixit VM1, Green S, Sarma V, Holzman LB, Wolf FW, O'Rourke K, Ward PA, Prochownik EV, Marks RM. (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. PMID: 2406243
2.Verstrepen L, Verhelst K, van Loo G, Carpentier I, Ley SC, Beyaert R. (2010) Expression, biological activities and mechanisms of action of A20 (TNFAIP3). Biochem Pharmacol. 80(12):2009-20. PMID: 20599425
3.Mele A, Cervantes JR, Chien V, Friedman D, Ferran C. (2014) Single nucleotide polymorphisms at the TNFAIP3/A20 locus and susceptibility/resistance to inflammatory and autoimmune diseases. Adv Exp Med Biol. 809:163-83. PMID: 25302371
4.Das T, Chen Z, Hendriks RW, Kool M. (2018) A20/Tumor Necrosis Factor alpha-Induced Protein 3 in Immune Cells Controls Development of Autoinflammation and Autoimmunity: Lessons from Mouse Models. Front Immunol. 9:104. PMID: 29515565
|Product By Gene ID
- EC 6.3.2.-
- TNF alpha-induced protein 3
- EC 18.104.22.168
- OTU domain-containing protein 7C
- tumor necrosis factor inducible protein A20
- Zinc finger protein A20
- tumor necrosis factor alpha-induced protein 3
- Putative DNA-binding protein A20
- tumor necrosis factor, alpha-induced protein 3