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.

Abstract	The zinc finger protein A20 is a tumor necrosis factor (TNF)- and interleukin 1 (IL-1)-inducible protein that negatively regulates nuclear factor-kappa B (NF-kappaB)-dependent gene expression. However, the molecular mechanism by which A20 exerts this effect is still unclear. We show that A20 does not inhibit TNF- induced nuclear translocation and DNA binding of NF-kappaB, although it completely prevents the TNF- induced activation of an NF-kappaB-dependent reporter gene, as well as TNF-induced IL-6 and granulocyte macrophage-colony stimulating factor gene expression. Moreover, NF-kappaB activation induced by overexpression of the TNF receptor-associated proteins TNF receptor-associated death domain protein (TRADD), receptor interacting protein (RIP), and TNF recep- tor-associated factor 2 (TRAF2) was also inhibited by expression of A20, whereas NF-kappaB activation induced by overexpression of NF-kappaB-inducing kinase (NIK) or the human T cell leukemia virus type 1 (HTLV-1) Tax was unaffected. These results demonstrate that A20 inhibits NF-kappaB-dependent gene expression by interfering with a novel TNF-induced and RIP- or TRAF2-mediated pathway that is different from the NIK-IkappaB kinase pathway and that is specifically involved in the transactivation of NF-kappaB. Via yeast two-hybrid screening, we found that A20 binds to a novel protein, ABIN, which mimics the NF-kappaB inhibiting effects of A20 upon overexpression, suggesting that the effect of A20 is mediated by its interaction with this NF-kappaB inhibiting protein, ABIN.
Authors	K Heyninck, D De Valck, W Vanden Berghe, W Van Criekinge, R Contreras, W Fiers, G Haegeman, R Beyaert
Journal	The Journal of cell biology (J Cell Biol) Vol. 145 Issue 7 Pg. 1471-82 (Jun 28 1999) ISSN: 0021-9525 [Print] United States
PMID	10385526 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Carrier Proteins DNA-Binding Proteins Gene Products, tax Interleukin-6 Intracellular Signaling Peptides and Proteins NF-kappa B Nuclear Proteins Proteins TNF Receptor-Associated Death Domain Protein TNF Receptor-Associated Factor 1 TNF Receptor-Associated Factor 2 Tradd protein, mouse Trans-Activators Tumor Necrosis Factor Receptor-Associated Peptides and Proteins Tumor Necrosis Factor-alpha Granulocyte-Macrophage Colony-Stimulating Factor DNA Protein Serine-Threonine Kinases RIPK1 protein, human Receptor-Interacting Protein Serine-Threonine Kinases Ripk1 protein, mouse Calcium-Calmodulin-Dependent Protein Kinases Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases NF-kappa B kinase TNFAIP3 protein, human Tumor Necrosis Factor alpha-Induced Protein 3 Cysteine Endopeptidases Tnfaip3 protein, mouse
Topics	Animals Calcium-Calmodulin-Dependent Protein Kinases (metabolism) Carrier Proteins (genetics, metabolism) Cell Line Cell Nucleus (drug effects, metabolism) Cysteine Endopeptidases DNA (genetics, metabolism) DNA-Binding Proteins Enzyme Activation (drug effects) Gene Products, tax (genetics, metabolism) Granulocyte-Macrophage Colony-Stimulating Factor (genetics) Humans Interleukin-6 (genetics) Intracellular Signaling Peptides and Proteins Mice Mitogen-Activated Protein Kinases Molecular Sequence Data NF-kappa B (antagonists & inhibitors, metabolism) Nuclear Proteins (genetics, physiology) Protein Binding (drug effects) Protein Serine-Threonine Kinases (genetics, metabolism) Proteins (chemistry, genetics, metabolism) Receptor-Interacting Protein Serine-Threonine Kinases Signal Transduction (drug effects) TNF Receptor-Associated Death Domain Protein TNF Receptor-Associated Factor 1 TNF Receptor-Associated Factor 2 Trans-Activators (genetics, physiology) Transcriptional Activation (drug effects) Tumor Necrosis Factor Receptor-Associated Peptides and Proteins Tumor Necrosis Factor alpha-Induced Protein 3 Tumor Necrosis Factor-alpha (antagonists & inhibitors, pharmacology) Yeasts (genetics) Zinc Fingers p38 Mitogen-Activated Protein Kinases

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