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.

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

J Cell Biol. 1999 Jun 28;145(7):1471-82. Unique Identifier : AIDSLINE GENBANK/AJ242778
Heyninck K; De Valck D; Vanden Berghe W; Van Criekinge W; Contreras R; Fiers W; Haegeman G; Beyaert R; Department of Molecular Biology, Flanders Interuniversity; Institute for Biotechnology, University of Ghent, B-9000 Ghent,; Belgium.

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.

Keywords: JOURNAL ARTICLE Animal Ca(2+)-Calmodulin Dependent Protein Kinase/METABOLISM Carrier Proteins/GENETICS/*METABOLISM Cell Line Cell Nucleus/DRUG EFFECTS/METABOLISM DNA/GENETICS/METABOLISM Enzyme Activation/DRUG EFFECTS Gene Products, tax/GENETICS/METABOLISM Granulocyte-Macrophage Colony-Stimulating Factor/GENETICS Human Interleukin-6/GENETICS Mice Molecular Sequence Data Nuclear Proteins/GENETICS/PHYSIOLOGY NF-kappa B/ANTAGONISTS & INHIB/*METABOLISM Protein Binding/DRUG EFFECTS Protein-Serine-Threonine Kinases/GENETICS/METABOLISM Proteins/CHEMISTRY/GENETICS/*METABOLISM Signal Transduction/DRUG EFFECTS Support, Non-U.S. Gov't *Trans-Activation (Genetics)/DRUG EFFECTS Trans-Activators/GENETICS/PHYSIOLOGY Tumor Necrosis Factor/*ANTAGONISTS & INHIB/PHARMACOLOGY Yeasts/GENETICS Zinc Fingers
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