J. Cell Biol., Volume 145, Number 7, June 28, 1999 1471-1482

The Zinc Finger Protein A20 Inhibits TNF-induced NF-B-dependent Gene Expression by Interfering with an RIP- or TRAF2-mediated Transactivation Signal and Directly Binds to a Novel NF-B-inhibiting Protein ABIN

Karen Heyninck, Dirk De Valck, Wim Vanden Berghe, Wim Van Criekinge, Roland Contreras, Walter Fiers, Guy Haegeman, and Rudi Beyaert

Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology, University of Ghent, B-9000 Ghent, Belgium

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-B)-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-B, although it completely prevents the TNF- induced activation of an NF-B-dependent reporter gene, as well as TNF-induced IL-6 and granulocyte macrophage-colony stimulating factor gene expression. Moreover, NF-B 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-B activation induced by overexpression of NF-B-inducing kinase (NIK) or the human T cell leukemia virus type 1 (HTLV-1) Tax was unaffected. These results demonstrate that A20 inhibits NF-B-dependent gene expression by interfering with a novel TNF-induced and RIP- or TRAF2-mediated pathway that is different from the NIK-IB kinase pathway and that is specifically involved in the transactivation of NF-B. Via yeast two-hybrid screening, we found that A20 binds to a novel protein, ABIN, which mimics the NF-B inhibiting effects of A20 upon overexpression, suggesting that the effect of A20 is mediated by its interaction with this NF-B inhibiting protein, ABIN.

A20;  ABIN;  nuclear factor-B;  tumor necrosis factor;  TRAF

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