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Molecular and Cellular Biology, July 2001, p. 4737-4747, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4737-4747.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Postrepression Activation of NF-kappa B Requires the Amino-Terminal Nuclear Export Signal Specific to Ikappa Balpha

Tony T. Huang and Shigeki Miyamoto*

Program in Molecular and Cellular Pharmacology, Department of Pharmacology, University of Wisconsin---Madison, Madison, Wisconsin 53706-1532

Received 31 January 2001/Accepted 24 April 2001

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

* Corresponding author. Mailing address: Department of Pharmacology, University of Wisconsin---Madison, 3795 Medical Sciences Center, 1300 University Avenue, Madison, WI 53706-1532. Phone: (608) 262-9281. Fax: (608) 262-1257. E-mail: smiyamot{at}facstaff.wisc.edu.

Molecular and Cellular Biology, July 2001, p. 4737-4747, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4737-4747.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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