FIG. 9.

Model for nuclear export-dependent cytoplasmic sequestration of NF-κB in unstimulated cells. Two central interpretations of our observations are pictorially represented in this figure. Numbers indicate steps, as explained below. First, cytoplasmic NF-κB–IκBα complexes are actively retained in the cytoplasm. We think this is needed because p65 can leak into the nucleus in the absence of stimulation, for example, because of constitutive turnover of IκBα (step 1). A Rel protein that is released due to constitutive degradation of its associated IκBα could, in principle, meet up with a newly synthesized IκBα molecule and be held back in the cytoplasm. We suggest that this does not happen to any significant extent, and the released p65 protein migrates to the nucleus (step 2). The second tenet of our model is that IκBα and p65 do not associate in the cytoplasm. Thus, newly synthesized IκBα translocates independently to the nucleus (step 3). Similarly, transiently released or newly synthesized p65 also migrates to the nucleus (step 4). The two proteins associate in the nucleus (step 5), from where the p65-IκBα complex is then exported out by CRM1 to maintain the cytosolic pool in unstimulated cells (step 6).