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

Institute of Molecular Medicine, Heinrich-Heine-University, D-40225 Düsseldorf, Germany.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2006; 281(18):12645-54. DOI: 10.1074/jbc.M511956200
Source: PubMed


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

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Available from: Reiner Jänicke, Jan 29, 2015
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    • "NFKBIZ encodes a novel member of the IκB family, IκB zeta. IκB zeta associates with both the p65 and p50 subunits of NF-κB and inhibits the transcriptional activity and DNA binding of NF-κB [12]. USP2 is a ubiquitin-specific protease which is required for the phosphorylation of IκB and functions as an additional positive regulator of TNF-α-induced NF-κB signaling [13]. "
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