Distinct Domains of IκBα Regulate c-Rel in the Cytoplasm and in the Nucleus

IκBα is a critical regulator of Rel/NF-κB-mediated gene activation. It controls the induction of NF-κB factors by retaining them in the cytoplasm and also functions in the nucleus to terminate the induction process. In this study, we show that IκBα regulates the transcriptional activity of c-Rel in the nuclear compartment. We also demonstrate that discrete functional domains of IκBα 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 IκBα and that the N-terminal domain of IκBα is required to mask the c-Rel nuclear localization signal. Importantly, IκBα 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 IκBα PEST domain. The mapping of the IκBα determinants that control the cytoplasmic and nuclear activities of c-Rel to specific regions of the molecule suggests that IκBα inhibitors could be designed to antagonize Rel/NF-κB activity in different subcellular compartments or at defined stages of activation.