I kappa B alpha and I kappa B alpha/NF-kappa B 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 t he cytoplasm by preventing the nuclear translocation of NF-kappaB and in th e nucleus where it dissociates NF-kappaB from DNA and transports it back to the cytoplasm, Cytoplasmic localization of inactive NF-kappaB/I kappaB alp ha 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 an choring of I kappaB alpha or NF-kappaB/I kappaB alpha complexes. The N-term inal domain of I kappaB alpha contains a sequence responsible for the cytop lasmic retention of I kappaB alpha that is specifically recognized by G3BP2 , a cytoplasmic protein that interacts with both IKB alpha and I kappaB alp ha /NF-kappaB complexes. G3BP2 is composed of an N-terminal domain homologo us to the NTF2 protein, followed by an acidic domain sufficient for the int eraction with the I kappaB alpha cytoplasmic retention sequence, a region c ontaining five PXXP motifs and a C-terminal domain containing RNA-binding m otifs. Overexpression of G3BP2 directly promotes retention of I kappaB alph a in the cytoplasm, indicating that subcellular distribution of I kappaB al pha and NF-kappaB/I kappaB alpha complexes likely results from a equilibriu m between nuclear import, nuclear export, and cytoplasmic retention. The mo lecular organization of G3BP2 suggests that this putative scaffold protein might connect the NF-kappaB signal transduction cascade with cellular funct ions such as nuclear transport or RNA metabolism.