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Molecular and Cellular Biology, December 2005, p. 10391-10406, Vol. 25, No. 23
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.23.10391-10406.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Exclusive Ubiquitination and Sumoylation on Overlapping Lysine Residues Mediate NF-{kappa}B Activation by the Human T-Cell Leukemia Virus Tax Oncoprotein{dagger}

Isabelle Lamsoul,1,2 Julie Lodewick,1 Sylvie Lebrun,1 Robert Brasseur,2 Arsène Burny,2 Richard B. Gaynor,3 and Françoise Bex1*

Institute for Microbiological Research J.-M. Wiame and Laboratory of Microbiology, Université Libre de Bruxelles, Brussels, Belgium,1 Faculté des Sciences Agronomiques de Gembloux, Gembloux, Belgium,2 Cancer Research and Clinical Investigation, Lilly Research Laboratories, Indianapolis, Indiana3

Received 29 April 2005/ Returned for modification 27 May 2005/ Accepted 15 September 2005

The transcription factor NF-{kappa}B is critical for the induction of cancer, including adult T-cell leukemia, which is linked to infection by human T-cell leukemia virus type 1 and the expression of its regulatory protein Tax. Although activation of the NF-{kappa}B pathway by Tax involves its interaction with the regulatory subunit of the I{kappa}B kinase (IKK) complex, NEMO/IKK{gamma}, the mechanism by which Tax activates specific cellular genes in the nucleus remains unknown. Here, we demonstrate that the attachment of SUMO-1 to Tax regulates its localization in nuclear bodies and the recruitment of both the RelA subunit of NF-{kappa}B and free IKK{gamma} in these nuclear structures. However, this sumoylation step is not sufficient for the activation of the NF-{kappa}B pathway by Tax. This activity requires the prior ubiquitination and colocalization of ubiquitinated Tax with IKK complexes in the cytoplasm and the subsequent migration of the RelA subunit of NF-{kappa}B to the nucleus. Thus, the ubiquitination and sumoylation of Tax function in concert to result in the migration of RelA to the nucleus and its accumulation with IKK{gamma} in nuclear bodies for activation of gene expression. These modifications may result in targets for the treatment of adult T-cell leukemia.

* Corresponding author. Mailing address: Institute for Microbiological Research J-M Wiame, 1 Avenue E. Gryson, B-1070 Brussels, Belgium. Phone: 32 2 526 72 86. Fax: 32 2 526 72 73. E-mail: fbex{at}ulb.ac.be.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2005, p. 10391-10406, Vol. 25, No. 23
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.23.10391-10406.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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