I kappa B epsilon, a novel member of the IκB family, controls RelA and cRel NF‐κB activity

We have isolated a human cDNA which encodes a novel IκB family member using a yeast two‐hybrid screen for proteins able to interact with the p52 subunit of the transcription factor NF‐κB. The protein is found in many cell types and its expression is up‐regulated following NF‐κB activation and during myelopoiesis. Consistent with its proposed role as an IκB molecule, IκB‐ϵ is able to inhibit NF‐κB‐directed transactivation via cytoplasmic retention of rel proteins. IκB‐ϵ translation initiates from an internal ATG codon to give rise to a protein of 45 kDa, which exists as multiple phosphorylated isoforms in resting cells. Unlike the other inhibitors, it is found almost exclusively in complexes containing RelA and/or cRel. Upon activation, IκB‐ϵ protein is degraded with slow kinetics by a proteasome‐dependent mechanism. Similarly to IκB‐α and IκB‐β, IκB‐ϵ contains multiple ankyrin repeats and two conserved serines which are necessary for signal‐induced degradation of the molecule. A unique lysine residue located N‐terminal of the serines appears to be not strictly required for degradation. Unlike IκB‐α and IκB‐β, IκB‐ϵ does not contain a C‐terminal PEST‐like sequence. IκB‐ϵ would, therefore, appear to regulate a late, transient activation of a subset of genes, regulated by RelA/cRel NF‐κB complexes, distinct from those regulated by other IκB proteins.