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

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.

ACKNOWLEDGMENTS

We thank D. Baltimore for IκBα knockout MEFs and p65 knockout 3T3 cells, D. Ballard for human p65 cDNA, S. Shumway for critical reading of the manuscript, and M. Yoshida for continued support and the generous gift of LMB.

This work was supported by an NIH predoctoral training grant award through the Molecular and Cellular Pharmacology graduate program to T.T.H. and NIH RO1 CA77474, a Howard Hughes Medical Institute fund through the University of Wisconsin Medical School, and the Shaw Scientist Award from the Milwaukee Foundation to S.M.