A novel IκB protein, IκB-ζ, induced by proinflammatory stimuli, negatively regulates nuclear factor-κB in the nuclei

The transcription factor nuclear factor-kappaB (NF-kappaB) plays crucial roles in a wide variety of cellular functions and its activity is strictly regulated by cytosolic inhibitors known as I kappa Bs. We here report a new member of the I kappaB protein family, I kappaB-zeta, harboring six ankyrin repeats at its carboxyl terminus. I kappaB-zeta mRNA is strongly induced after stimulation by lipopolysaccharide. The induction of I kappaB-zeta is also observed by stimulation with interleukin-1 beta but not by tumor necrosis factor-alpha. In contrast to cytosolic I kappaB-alpha, -beta, and -epsilon, the induced I kappaB-zeta localizes in the nucleus via its amino-terminal region, which shows no homology with other proteins. Transiently expressed I kappaB-zeta inhibits the NF-kappaB activity without affecting the nuclear translocation of NF-kappaB upon stimulation. The expressed I kappaB-zeta preferentially associates with the NF-kappaB subunit p50 rather than p65 and recombinant I kappaB-zeta proteins inhibit the DNA binding of the p65/p50 heterodimer and the p50/p50 homodimer, Thus, I kappaB-zeta negatively regulates NF-kappaB activity in the nucleus, possibly in order to prevent excessive inflammation. Moreover, transfection of I kappaB-zeta renders cells more susceptible to apoptosis induced by tumor necrosis factor-alpha. The proapoptotic activity of I kappaB-zeta further suggests that it might be one of key regulators for inflammation and other biologically relevant processes.