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

I kappaB alpha inhibits the transcriptional activity of NF-kappaB both in the cytoplasm by preventing the nuclear translocation of NF-kappaB and in the nucleus where it dissociates NF-kappaB from DNA and transports it back to the cytoplasm, Cytoplasmic localization of inactive NF-kappaB/I kappaB alpha complexes is controlled by mutual masking of nuclear import sequences of NF-kappaB p65 and I kappaB alpha and active CRM1-mediated nuclear export. Here, we describe an additional mechanism accounting for the cytoplasmic anchoring of I kappaB alpha or NF-kappaB/I kappaB alpha complexes. The N-terminal domain of I kappaB alpha contains a sequence responsible for the cytoplasmic retention of I kappaB alpha that is specifically recognized by G3BP2, a cytoplasmic protein that interacts with both IKB alpha and I kappaB alpha /NF-kappaB 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 I kappaB alpha 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 I kappaB alpha in the cytoplasm, indicating that subcellular distribution of I kappaB alpha and NF-kappaB/I kappaB alpha 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-kappaB signal transduction cascade with cellular functions such as nuclear transport or RNA metabolism.