Postrepression Activation of NF-κB Requires the Amino-Terminal Nuclear Export Signal Specific to IκBα

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Abstract
One of the most prominent NF-κB target genes in mammalian cells is the gene encoding one of its inhibitor proteins, IκBα. The increased synthesis of IκBα leads to postinduction repression of nuclear NF-κB activity. However, it is unknown why IκBα, among multiple IκB family members, is involved in this process and what significance this feedback regulation has beyond terminating NF-κB activity. Herein, we report an important IκBα-specific function dictated by its amino-terminal nuclear export sequence (N-NES). The IκBα N-NES is necessary for the postinduction export of nuclear NF-κB, which is a critical event in reestablishing a permissive condition for NF-κB to be rapidly reactivated. We show that although IκBα and another IκB member, IκBβ, can enter the nucleus and repress NF-κB DNA-binding activity during the postinduction phase, only IκBα allows the efficient export of nuclear NF-κB. Moreover, swapping the N-terminal region of IκBβ for the corresponding IκBα sequence is sufficient for the IκB chimera protein to export NF-κB similarly to IκBα during the postinduction state. Our findings provide a mechanistic explanation of why IκBα but not other IκB members is crucial for postrepression activation of NF-κB. We propose that this IκBα-specific function is important for certain physiological and pathological conditions where NF-κB needs to be rapidly reactivated.