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

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-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-B pathway by Tax involves its interaction with the regulatory subunit of the IB kinase (IKK) complex, NEMO/IKK, 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-B and free IKK in these nuclear structures. However, this sumoylation step is not sufficient for the activation of the NF-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-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 in nuclear bodies for activation of gene expression. These modifications may result in targets for the treatment of adult T-cell leukemia.

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