IκBα and IκBα/NF-κB complexes are retained in the cytoplasm through interaction with a novel partner, RasGAP SH3-binding protein 2

Abstract

IκBα inhibits the transcriptional activity of NF-κB both in the cytoplasm by preventing the nuclear translocation of NF-κB and in the nucleus where it dissociates NF-κB from DNA and transports it back to the cytoplasm. Cytoplasmic localization of inactive NF-κB/IκBα complexes is controlled by mutual masking of nuclear import sequences of NF-κB p65 and IκBα and active CRM1-mediated nuclear export. Here, we describe an additional mechanism accounting for the cytoplasmic anchoring of IκBα or NF-κB/IκBα complexes. The N-terminal domain of IκBα contains a sequence responsible for the cytoplasmic retention of IκBα that is specifically recognized by G3BP2, a cytoplasmic protein that interacts with both IκBα and IκBα/NF-κB complexes. G3BP2 is composed of an N-terminal domain homologous to the NTF2 protein, followed by an acidic domain sufficient for the interaction with the IκBα cytoplasmic retention sequence, a region containing five PXXP motifs and a C-terminal domain containing RNA-binding motifs. Overexpression of G3BP2 directly promotes retention of IκBα in the cytoplasm, indicating that subcellular distribution of IκBα and NF-κB/IκBα complexes likely results from a equilibrium between nuclear import, nuclear export, and cytoplasmic retention. The molecular organization of G3BP2 suggests that this putative scaffold protein might connect the NF-κB signal transduction cascade with cellular functions such as nuclear transport or RNA metabolism.