I-KAPPA-B-EPSILON, A NOVEL MEMBER OF THE I-KAPPA-B-FAMILY, CONTROLS RELA AND CREL NF-KAPPA-B-ACTIVITY

We have isolated a human cDNA which encodes a novel I kappa B family m ember using a yeast two-hybrid screen for proteins able to interact wi th the p52 subunit of the transcription factor NF-kappa B. The protein is found in many cell types and its expression is up-regulated follow ing NF-kappa B activation and during myelopoiesis. Consistent with its proposed role as an I kappa B molecule, I kappa B-epsilon is able to inhibit NF-kappa B-directed transactivation via cytoplasmic retention of rel proteins. I kappa B-epsilon translation initiates from an inter nal ATG codon to give rise to a protein of 45 kDa, which exists as mul tiple phosphorylated isoforms in resting cells. Unlike the other inhib itors, it is found almost exclusively in complexes containing RelA and /or cRel. Upon activation, I kappa B-epsilon protein is degraded with slow kinetics by a proteasome-dependent mechanism. Similarly to I kapp a B-alpha and I kappa B-beta, I kappa B-epsilon contains multiple anky rin repeats and two conserved serines which are necessary for signal-i nduced degradation of the molecule. A unique lysine residue located N- terminal of the serines appears to be not strictly required for degrad ation, Unlike I kappa B-alpha and I kappa B-beta, I kappa B-epsilon do es not contain a C-terminal PEST-like sequence. I kappa B-epsilon woul d, therefore, appear to regulate a late, transient activation of a sub set of genes, regulated by RelA/cRel NF-kappa B complexes, distinct fr om those regulated by other I kappa B proteins.