IkappaBalpha and IkappaBalpha /NF-kappa B complexes are retained in the cytoplasm through interaction with a novel partner, RasGAP SH3-binding protein 2.
IkappaBalpha 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/IkappaBalpha complexes is controlled by mutual masking of nuclear import sequences of NF-kappaB p65 and IkappaBalpha and active CRM1-mediated nuclear export. Here, we describe an additional mechanism accounting for the cytoplasmic anchoring of IkappaBalpha or NF-kappaB/IkappaBalpha complexes. The N-terminal domain of IkappaBalpha contains a sequence responsible for the cytoplasmic retention of IkappaBalpha that is specifically recognized by G3BP2, a cytoplasmic protein that interacts with both IkappaBalpha and IkappaBalpha/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 IkappaBalpha 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 IkappaBalpha in the cytoplasm, indicating that subcellular distribution of IkappaBalpha and NF-kappaB/IkappaBalpha 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.
Prigent
M
M
Laboratoire de Transport Nucleocytoplasmique, Institut Curie-CNRS UMR144, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Barlat
I
I
Langen
H
H
Dargemont
C
C
D048868:Adaptor Proteins, Signal Transducing; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D004265:DNA Helicases; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins; D046911:Macromolecular Substances; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D019913:Nuclear Localization Signals / Q000235:genetics / Q000502:physiology; D000075223:Poly-ADP-Ribose Binding Proteins; D011233:Precipitin Tests; D011485:Protein Binding; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D016601:RNA-Binding Proteins; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C574606:G3BP2 protein, human; D020672:I-kappa B Proteins; D046911:Macromolecular Substances; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D019913:Nuclear Localization Signals; D000075223:Poly-ADP-Ribose Binding Proteins; D021382:Protein Sorting Signals; D000067776:RNA Recognition Motif Proteins; D016601:RNA-Binding Proteins; D011965:Receptors, Glucocorticoid; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000072000:NF-KappaB Inhibitor alpha; D011770:Pyruvate Kinase; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases