Identification of a novel A20-binding inhibitor of nuclear factor-kappa B activation termed ABIN-2

The nuclear factor kappaB (NF-kappaB) plays a central role in the regulatio n of genes implicated immune responses, inflammatory processes, and apoptot ic cell death. The zinc finger protein A20 is a cellular inhibitor of NF-ka ppaB activation by various stimuli and plays a critical role in terminating NF-kappaB responses. The underlying mechanism for NF-kappaB inhibition by A20 is still unknown. A20 has been shown to interact with several proteins including tumor necrosis factor (TNF) receptor-associated factors 2 and 6, as well as the inhibitory protein of kappaB kinase (IKK) gamma protein. Her e we report the cloning and characterization of ABIN-2, a previously unknow n protein that binds to the COOH-terminal zinc finger domain of A20. NF-kap paB activation induced by TNF and interleukin-1 is inhibited by overexpress ion. of ABIN-2. The latter also inhibits NF-kappaB activation induced by ov erexpression of receptor-interacting protein or TNF receptor-associated fac tor 2. In contrast, NF-kappaB activation by overexpression of IKK beta or d irect activators of the IKK complex, such as Tax, cannot be inhibited by AB IN-2. These results indicate that ABIN-2 interferes with NF-kappaB activati on upstream of the IKK complex and that it might contribute to the NF-kappa B-inhibitory function of A20.