Exclusive Ubiquitination And Sumoylation On Overlapping Lysine Residues Mediate Nf-Kappa B Activation By The Human T-Cell Leukemia Virus Tax Oncoprotein

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