The zinc finger protein A20 inhibits TNF-induced NF-kappa B-dependent geneexpression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappa B-inhibiting protein ABIN
K. Heyninck et al., The zinc finger protein A20 inhibits TNF-induced NF-kappa B-dependent geneexpression by interfering with an RIP- or TRAF2-mediated transactivation signal and directly binds to a novel NF-kappa B-inhibiting protein ABIN, J CELL BIOL, 145(7), 1999, pp. 1471-1482
The zinc finger protein A20 is a tumor necrosis factor (TNF)- and interleuk
in 1 (IL-1)-inducible protein that negatively regulates nuclear factor-kapp
a B (NF-kappa B)-dependent gene expression, However, the molecular mechanis
m by which A20 exerts this effect is still unclear, We show that A20 does n
ot inhibit TNF-induced nuclear translocation and DNA binding of NF-kappa B,
although it completely prevents the TNF-induced activation of an NF-kappa
B-dependent reporter gene, as well as TNF-induced IL-6 and granulocyte macr
ophage-colony stimulating factor gene expression, Moreover, NF-kappa B acti
vation induced by overexpression of the TNF receptor-associated proteins TN
F receptor-associated death domain protein (TRADD), receptor interacting pr
otein (RIP), and TNF receptor-associated factor 2 (TRAF2) was also inhibite
d by expression of A20, whereas NF-kappa B activation induced by overexpres
sion of NF-kappa B-inducing kinase (NIK) or the human T cell leukemia virus
type 1 (HTLV-1) Tax was unaffected. These results demonstrate that A20 inh
ibits NF-kappa B-dependent gene expression by interfering with a novel TNF-
induced and RIP- or TRAF2-mediated pathway that is different from the NIK-I
kappa B kinase pathway and that is specifically involved in the transactiv
ation of NF-kappa B, Via yeast two-hybrid screening, we found that A20 bind
s to a novel protein, ABIN, which mimics the NF-kappa B inhibiting effects
of A20 upon overexpression, suggesting that the effect of A20 is mediated b
y its interaction with this NF-kappa B inhibiting protein, ABIN.