© The Rockefeller University Press,
0021-9525/1999//1471 $5.00
The Journal of Cell Biology, Volume 145, Number 7,
, 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–I
B 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.
Key Words: A20 ABIN nuclear factor-
B tumor necrosis factor TRAF
Abbreviations used in this paper: ABIN, A20 binding inhibitor of NF-
B activation; CBP, CREB (cAMP responsive element binding protein) binding protein; GFP, green fluorescent protein; GM-CSF, granulocyte macrophage–colony stimulating factor; HTLV-1, human T cell leukemia virus type 1; IKK, I
B kinase; IL, interleukin; MAP kinase, mitogen-activated protein kinase; NF-
B, nuclear factor-kappa B; NIK, NF-
B–inducing kinase; RIP, receptor interacting protein; SRE, serum response element; TNF, tumor necrosis factor; TPA, tetradecanoic phorbol acetate; TRADD, TNF receptor–associated death domain protein; TRAF, TNF receptor–associated factor.
R. Beyaert, G. Haegeman, and R. Contreras are a postdoctoral research assistant and research directors with the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, respectively. Research was supported by the Interuniversitaire Attractiepolen, the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, the Sportvereniging tegen Kanker, European Community–Biomed2 grant and a European Community–Training and Mobility Research grant.
D. De Valck's present address is Laboratory of Skeletal Developments and Joint Disorders, Catholic University of Leuven, B-3000 Leuven, Belgium. W. Van Criekinge's present address is Devgen, Technologiepark, B-9052 Zwijnaarde, Belgium.

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