The IkappaBalpha and IkappaBbeta proteins inhibit the transcriptional potential of active NF-kappaB dimers through stable complex formation. It has been shown that inactive IkappaBalpha x NF-kappaB complexes shuttle in and out of the nucleus, whereas IkappaBbeta x NF-kappaB complexes are retained exclusively in the cytoplasm of resting cells. The biochemical mechanism underlying this functional difference and its consequences are unknown. Although the two IkappaB proteins are significantly homologous, IkappaBbeta contains a unique 47-amino acid insertion of unknown function within its ankyrin repeat domain. In this study, we assess the role of the IkappaBbeta insert in regulating cytoplasmic retention of IkappaBbeta.NF-kappaB complexes. Deletion of the IkappaBbeta insert renders IkappaBbeta x NF-kappaB complexes capable of shuttling between the nucleus and cytoplasm, similar to IkappaBalpha x NF-kappaB complexes. A small Ras-like G-protein, kappaB-Ras, participates with the IkappaBbeta insert to effectively mask the NF-kappaB nuclear localization potential. Similarly, a complex between NF-kappaB and a mutant IkappaBbeta protein containing four serine to alanine mutations within its C-terminal proline, glutamic acid, serine, and threonine-rich sequence exhibits nucleocytoplasmic shuttling. This suggests a phosphorylation state-dependent role for the C-terminal proline, glutamic acid, serine, and threonine-rich sequence of IkappaBbeta in proper localization of IkappaBbeta x NF-kappaB complexes. These results are consistent with structural studies, which predicted that binary IkappaBbeta x NF-kappaB complexes should be capable of nuclear translocation, and with previous observations that hypophosphorylated IkappaBbeta.NF-kappaB complexes can reside in the nucleus.
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