A novel member of the IκB family, human IκB-ζ, inhibits transactivation of p65 and its DNA binding

A novel member of the I kappa B family, human I kappa B-zeta, was identified by a differential screening approach of apoptosis-sensitive and -resistant tumor cells. The protein consists of 6 ankyrin repeats at its COOH terminus and shares about 30% identity with other I kappa B members. I kappa B-zeta associates with both the p65 and p50 subunit of NF-kappa B and inhibits the transcriptional activity as well as the DNA binding of the transcription factor. Interestingly, I kappa B-zeta is localized in the nucleus where it aggregates in matrix-associated deacetylase bodies, indicating that I kappa B-zeta regulates nuclear NF-kappa B activity rather than its nuclear translocation from the cytoplasm. I kappa B-zeta expression itself was regulated by NF-kappa B, suggesting that its activity is controlled in a negative feedback loop. Unlike classical I kappa B proteins, I kappa B-zeta was not degraded upon cell stimulation. Treatment with tumor necrosis factor-alpha, interleukin-1 beta, and lipopolysaccharide induced a strong induction of I kappa B-zeta transcripts. Expression of I kappa B-zeta was detected in different tissues including lung, liver, and in leukocytes but not in the brain. Suppression of endogenous I kappa B-zeta by RNA interference rendered cells more resistant to apoptosis, whereas overexpression of I kappa B-zeta was sufficient to induce cell death. Our results, therefore, suggest that I kappa B-zeta functions as an additional regulator of NF-kappa B activity and, hence, provides another control level for the activation of NF-kappa B-dependent target genes.