Distinct domains of IκBα regulate c-Rel in the cytoplasm and in the nucleus

I kappa B alpha is a critical regulator of Rel/NF-kappa B-mediated gene activation. It controls the induction of NF-kappa B factors by retaining them in the cytoplasm and also functions in the nucleus to terminate the induction process. In this study, we show that I kappa B alpha regulates the transcriptional activity of c-Rel in the nuclear compartment. We also demonstrate that discrete functional domains of I kappa B alpha are responsible for the cytoplasmic and nuclear regulation of c-Rel. We show that the determinants for the cytoplasmic regulation of c-Rel reside in the N-terminal and central ankyrin regions of I kappa B alpha and that the N-terminal domain of I kappa B alpha is required to mask the c-Rel nuclear localization signal. Importantly, I kappa B alpha sequences necessary to regulate c-Rel in the nucleus map to its central ankyrin domain and to a few negatively charged amino acids that immediately follow in the C-terminal I kappa B alpha PEST domain. The mapping of the I kappa B alpha determinants that control the cytoplasmic and nuclear activities of c-Rel to specific regions of the molecule suggests that I kappa B alpha inhibitors could be designed to antagonize Rel/NF-kappa B activity in different subcellular compartments or at defined stages of activation.