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  • Original Paper
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UVDDB p127-binding modulates activities and intracellular distribution of Hepatitis B virus X protein

Oncogene volume 19, pages 4417–4426 (2000)Cite this article

Abstract

Mammalian hepatitis B viruses encode a unique regulatory protein termed X, which is essential for infection and likely plays a role in the carcinogenic process associated with hepadnaviral infection. Among the numerous properties ascribed to X protein, two have been widely documented: promiscuous transcriptional transactivation and proapoptosis. However, full understanding of the mechanisms underlying these activities requires the identification of the genuine X partners among the multiple X-binding host proteins. Here we show that (i) mutations in X protein, which markedly alter affinity for the host protein UVDDBp127, inactivate both transactivation and proapoptosis; (ii) ectopic fusion of a functional UVDDB-binding domain to a deficient binding X mutant restored its activity; (iii) in contrast to the loss-of-binding mutants, a mutant with a strong gain-of-binding exerted trans-dominant negative effects on wt X activity and localized in the nucleus and (iv) increase in intracellular UVDDB concentration enhanced both wt X-mediated transactivation and apoptosis. Taken together, our data provide strong evidence for a common upstream step in X mode of action, consisting of its productive interaction with UVDDB, via a structurally and functionally autonomous module. In addition, they underscore a nuclear location step of the viral protein that depends on its ability to bind UVDDB.

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Acknowledgements

D Sitterlin was supported by fellowships from the ‘Ministre de l'Education Nationale et de la Recherche' and the ‘Fondation pour la Recherche Médicale'. We are grateful to WS Mason for providing anti-WHx antibodies. We are indebted to M Levrero's Laboratory for help in setting up the X transactivation assay during D Sitterlin training period supported by a short term EMBO fellowship. We thank for E Perret for help in confocal microscope analysis and C Legout for the preparation of yeast media. We thank S Whiteside, M Rosbash, F Lehembre, M Flajolet and Yu Wei for helpful suggestions and critical reading of the manuscript. We are grateful to many members of the laboratory for support, especially P Tiollais, director of the Research Unit.

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  1. Delphine Sitterlin

    Present address: EMBL, meyerhofstr. 1, Heidelberg, D-69117, Germany

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  1. Institut Pasteur, Unité de recombinaison et expression génétique (INSERM U163), 28 rue du Dr Roux 75724, Paris, Cedex 15, France

    Delphine Sitterlin, Françoise Bergametti & Catherine Transy

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Sitterlin, D., Bergametti, F. & Transy, C. UVDDB p127-binding modulates activities and intracellular distribution of Hepatitis B virus X protein. Oncogene 19, 4417–4426 (2000). https://doi.org/10.1038/sj.onc.1203771

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