A Novel Member of the IκB Family, Human IκB-ζ, Inhibits Transactivation of p65 and Its DNA Binding

• Published in: The Journal of biological chemistry 2006-05, Vol.281 (18), p.12645
• Main Authors: Gudrun Totzke, Frank Essmann, Stephan Pohlmann, Charlotte Lindenblatt, Reiner U. Jänicke, Klaus Schulze-Osthoff
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M511956200

A novel member of the IκB family, human IκB-ζ, 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 IκB members. IκB-ζ associates with both the p65 and p50 subunit of NF-κB and inhibits the transcriptional activity as well as the DNA binding of the transcription factor. Interestingly, IκB-ζ is localized in the nucleus where it aggregates in matrix-associated deacetylase bodies, indicating that IκB-ζ regulates nuclear NF-κB activity rather than its nuclear translocation from the cytoplasm. IκB-ζ expression itself was regulated by NF-κB, suggesting that its activity is controlled in a negative feedback loop. Unlike classical IκB proteins, IκB-ζ was not degraded upon cell stimulation. Treatment with tumor necrosis factor-α, interleukin-1β, and lipopolysaccharide induced a strong induction of IκB-ζ transcripts. Expression of IκB-ζ was detected in different tissues including lung, liver, and in leukocytes but not in the brain. Suppression of endogenous IκB-ζ by RNA interference rendered cells more resistant to apoptosis, whereas overexpression of IκB-ζ was sufficient to induce cell death. Our results, therefore, suggest that IκB-ζ functions as an additional regulator of NF-κB activity and, hence, provides another control level for the activation of NF-κB-dependent target genes.