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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-
B Activation by the Human T-Cell Leukemia Virus Tax Oncoprotein
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-
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 I
B 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.
* 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.
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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