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J. Cell Biol.,
Volume 145, Number 7, June 28, 1999 1471-1482
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
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.
B;
tumor
necrosis factor;
TRAF
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