Abstract
Control over the nuclear localization of nuclear factor kappaB/Rel proteins is accomplished in large part through association with members of the inhibitor of kappaB (IkappaB) protein family. For example, the well studied IkappaBalpha protein actively shuttles between the nucleus and the cytoplasm and both inhibits nuclear import and mediates nuclear export of NF-kappaB/Rel proteins. In contrast, the IkappaBbeta protein can inhibit nuclear import of NF-kappaB/Rel proteins but does not remove NF-kappaB/Rel proteins from the nucleus. To further understand how the IkappaB proteins control the nuclear-cytoplasmic distribution of NF-kappaB/Rel proteins, we have characterized the nuclear import and nuclear export functions of IkappaBepsilon. Our results indicate that the IkappaBepsilon protein, like the IkappaBalpha protein, actively shuttles between the nucleus and the cytoplasm. Similar to IkappaBalpha, nuclear import of IkappaBepsilon is mediated by its ankyrin repeat domain and is not blocked by the dominant-negative RanQ69L protein. However, the nuclear import function of the IkappaBepsilon ankyrin repeat domain is markedly less efficient than that of IkappaBalpha, with the result that nuclear shuttling of IkappaBepsilon between the nucleus and the cytoplasm is significantly slower than IkappaBalpha. Nuclear export of IkappaBepsilon is mediated by a short leucine-rich nuclear export sequence (NES)-like sequence ((343)VLLPFDDLKI(352)), located between amino acids 343 and 352. This NES-like sequence is required for RanGTP-dependent binding of IkappaBepsilon to CRM1. Nuclear accumulation of IkappaB(epsilon) is increased by either leptomycin B treatment or alanine substitutions within the IkappaBepsilon-derived NES. A functional NES is required for both efficient cytoplasmic retention and post-induction control of c-Rel by IkappaBepsilon, consistent with the notion that IkappaBepsilon-mediated nuclear export contributes to control over the nucleocytoplasmic distribution of NF-kappaB/Rel proteins.
Highlights
The IB proteins were first identified as cytoplasmic inhibitors of NF-B/Rel proteins, it is clear that IB proteins act in the nucleus
Nuclear import of IB␣ is mediated by sequences within the ankyrin repeat domain and does not require the importin-␣/importin- nuclear import complex utilized by conventional nuclear localization sequences (NLSs)1 (26)
Nuclear Import of IB⑀ in Digitonin-permeabilized HeLa Cells—The IB⑀ protein is located in the cytoplasm, yet shares along with IB␣ and IB a central ankyrin repeat domain that is responsible for nuclear import of IB␣ (Fig. 1) (29)
Summary
The IB proteins were first identified as cytoplasmic inhibitors of NF-B/Rel proteins, it is clear that IB proteins act in the nucleus. The well studied IB␣ protein actively shuttles between the nucleus and the cytoplasm and both inhibits nuclear import and mediates nuclear export of NF-B/Rel proteins. The nuclear import function of the IB⑀ ankyrin repeat domain is markedly less efficient than that of IB␣, with the result that nuclear shuttling of IB⑀ between the nucleus and the cytoplasm is significantly slower than IB␣.
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