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J. Biol. Chem., Vol. 280, Issue 16, 15942-15951, April 22, 2005

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NF-B Is Transported into the Nucleus by Importin 3 and Importin 4^*

Riku Fagerlund, Leena Kinnunen¶, Matthias Köhler||**, Ilkka Julkunen, and Krister Melén

From the Departments of Viral Diseases and Immunology and ^¶Epidemiology and Health Promotion, National Public Health Institute, FIN-00300, Helsinki, Finland, the ^||Max Delbrueck Center for Molecular Medicine, 13125 Berlin, Germany, and the ^**Center for Nephrology and Hypertension, Ostsee Clinic Damp, 24351 Damp, Germany

NF-B transcription factors are retained in the cytoplasm in an inactive form until they are activated and rapidly imported into the nucleus. We identified importin 3 and importin 4 as the main importin isoforms mediating TNF--stimulated NF-B p50/p65 heterodimer translocation into the nucleus. Importin 3 and 4 are close relatives in the human importin family. We show that importin 3 isoform also mediates nuclear import of NF-B p50 homodimer in nonstimulated cells. Importin 3 is shown to directly bind to previously characterized nuclear localization signals (NLSs) of NF-B p50 and p65 proteins. Importin molecules are known to have armadillo repeats that constitute the N-terminal and C-terminal NLS binding sites. We demonstrate by site-directed mutagenesis that NF-B p50 binds to the N-terminal and p65 to the C-terminal NLS binding site of importin 3. In vitro competition experiments and analysis of cellular NF-B suggest that NF-B binds to importin only when it is free of IB. The present study demonstrates that the nuclear import of NF-B is a highly regulated process mediated by a subset of importin molecules.

Received for publication, January 24, 2005

^* This study was supported by grants from the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Cancer Foundation, the Research and Science Foundation of Farmos, the European Commission (QLK2-CT-2002-00954), and the Finnish Cultural Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Laboratory of Infectious Disease Immunology, Dept. of Viral Diseases and Immunology, National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland. Tel.: 358-9-47448365; Fax: 358-9-47448355; E-mail: riku.fagerlund{at}ktl.fi.

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