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Molecular and Cellular Biology, March 2000, p. 2269-2284, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Cytoplasmic Sequestration of Rel Proteins by Ikappa Balpha Requires CRM1-Dependent Nuclear Export

Winnie F. Tam,1,2 Linda H. Lee,1,2,dagger Laura Davis,3 and Ranjan Sen1,2,*

Rosenstiel Basic Medical Sciences Research Center,1 Department of Biology,2 and W. M. Keck Institute for Cellular Visualization,3 Brandeis University, Waltham, Massachusetts 02454

Received 29 July 1999/Returned for modification 16 September 1999/Accepted 7 December 1999

Rel and Ikappa B protein families form a complex cellular regulatory network. A major regulatory function of Ikappa B proteins is to retain Rel proteins in the cell cytoplasm. In addition, Ikappa B proteins have also been postulated to serve nuclear functions. These include the maintenance of inducible NF-kappa B-dependent gene transcription, as well as termination of inducible transcription. We show that Ikappa Balpha shuttles between the nucleus and the cytoplasm, utilizing the nuclear export receptor CRM1. A CRM1-binding export sequence was identified in the N-terminal domain of Ikappa Balpha but not in that of Ikappa Bbeta or Ikappa Bvarepsilon . By reconstituting major aspects of NF-kappa B-Ikappa B sequestration in yeast, we demonstrate that cytoplasmic retention of p65 (also called RelA) by Ikappa Balpha requires Crm1p-dependent nuclear export. In mammalian cells, inhibition of CRM1 by leptomycin B resulted in nuclear localization of cotransfected p65 and Ikappa Balpha in COS cells and enhanced nuclear relocation of endogenous p65 in T cells. These observations suggest that the main function of Ikappa Balpha is that of a nuclear export chaperone rather than a cytoplasmic tether. We propose that the nucleus is the major site of p65-Ikappa Balpha association, from where these complexes must be exported in order to create the cytoplasmic pool.

* Corresponding author. Mailing address: Rosenstiel Basic Medical Sciences Research Center and Department of Biology, Brandeis University, Waltham, MA 02454. Phone: (781) 736-2455. Fax: (781) 736-2405. E-mail: sen{at}brandeis.edu.

dagger Present address: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710.

Molecular and Cellular Biology, March 2000, p. 2269-2284, Vol. 20, No. 6
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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