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

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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 I $kappa$ B $alpha$

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 importantrole in HBV-associated hepatocarcinogenesis. It has been suggestedthat X acts as a nuclear coactivator or stimulates several signaltransduction pathways by acting in the cytoplasm. One of thesepathways leads to the nuclear translocation of NF- $kappa$ B. A recentreport indicates that X activates NF- $kappa$ B by acting on two cytoplasmicinhibitors of this family of transcription factors: I $kappa$ B $alpha$ and theprecursor/inhibitor p105. We demonstrate here that X directlyinteracts with I $kappa$ B $alpha$ , which is able to transport it to the nucleusby a piggyback mechanism. This transport requires a region ofI $kappa$ B $alpha$ (the second ankyrin repeat) which has been demonstrated tobe involved in its nuclear import following NF- $kappa$ B activation.Using deletion mutants, we showed that amino acids 249 to 253of I $kappa$ B $alpha$ (located in the C-terminal part of the sixth ankyrin repeat)play a critical role in the interaction with X. This small regionoverlaps one of the domains of I $kappa$ B $alpha$ mediating the interactionwith the p50 and p65 subunits of NF- $kappa$ B and is also close to thenuclear export sequence of I $kappa$ B $alpha$ , therefore providing a potentialexplanation for the nuclear accumulation of I $kappa$ B $alpha$ with X. Thisassociation can also be observed upon the induction of endogenousI $kappa$ B $alpha$ by tumor necrosis factor alpha (TNF- $alpha$ ) treatment of Changcells expressing X. In accordance with this observation, bandshift analysis indicates that X induces a sustained NF- $kappa$ B activationfollowing TNF- $alpha$ treatment, probably by preventing the reassociationof newly synthesized nuclear I $kappa$ B $alpha$ with DNA-bound NF- $kappa$ Bcomplexes.

^* 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: 33 145 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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