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Molecular and Cellular Biology, September 1999, p. 6345-6354, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Direct Association and Nuclear Import of the Hepatitis B Virus X Protein with the NF-kappa B Inhibitor Ikappa Balpha

Robert Weil,1 Hüseyin Sirma,2 Carlo Giannini,2 Dina Kremsdorf,2 Christine Bessia,1 Catherine Dargemont,3 Christian Bréchot,2 and Alain Israël1,*

Unité de Biologie Moléculaire de l'Expression Génique, URA 1773 Centre National de la Recherche Scientifique, Institut Pasteur, 75724 Paris Cedex 15,1 INSERM U370, Carcinogénèse Hépatique et Virologie Moléculaire, Institut Necker, 75015 Paris,2 and Laboratoire de Transport Nucléocytoplasmique, UMR 144 Institut Curie-CNRS, 75231 Paris Cedex 05,3 France

Received 2 February 1999/Returned for modification 25 March 1999/Accepted 27 May 1999

The X protein of hepatitis B virus (HBV) is a transcriptional activator which is required for infection and may play an important role in HBV-associated hepatocarcinogenesis. It has been suggested that X acts as a nuclear coactivator or stimulates several signal transduction pathways by acting in the cytoplasm. One of these pathways leads to the nuclear translocation of NF-kappa B. A recent report indicates that X activates NF-kappa B by acting on two cytoplasmic inhibitors of this family of transcription factors: Ikappa Balpha and the precursor/inhibitor p105. We demonstrate here that X directly interacts with Ikappa Balpha , which is able to transport it to the nucleus by a piggyback mechanism. This transport requires a region of Ikappa Balpha (the second ankyrin repeat) which has been demonstrated to be involved in its nuclear import following NF-kappa B activation. Using deletion mutants, we showed that amino acids 249 to 253 of Ikappa Balpha (located in the C-terminal part of the sixth ankyrin repeat) play a critical role in the interaction with X. This small region overlaps one of the domains of Ikappa Balpha mediating the interaction with the p50 and p65 subunits of NF-kappa B and is also close to the nuclear export sequence of Ikappa Balpha , therefore providing a potential explanation for the nuclear accumulation of Ikappa Balpha with X. This association can also be observed upon the induction of endogenous Ikappa Balpha by tumor necrosis factor alpha (TNF-alpha ) treatment of Chang cells expressing X. In accordance with this observation, band shift analysis indicates that X induces a sustained NF-kappa B activation following TNF-alpha treatment, probably by preventing the reassociation of newly synthesized nuclear Ikappa Balpha with DNA-bound NF-kappa B complexes.

* Corresponding author. Mailing address: Unité de Biologie Moléculaire de l'Expression Génique, URA 1773 CNRS, Institut Pasteur, 25 Rue du Dr. Roux, 75724 Paris Cedex 15, France. Phone: 33 1 45 68 85 53. Fax: 33 1 40 61 30 40. E-mail: aisrael{at}pasteur.fr.

Molecular and Cellular Biology, September 1999, p. 6345-6354, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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