Exclusive ubiquitination and sumoylation on overlapping lysine residues mediate NF-kappaB 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.
Lamsoul
Isabelle
I
Institute for Microbiological Research J-M Wiame, 1 Avenue E. Gryson, B-1070 Brussels, Belgium.
Lodewick
Julie
J
Lebrun
Sylvie
S
Brasseur
Robert
R
Burny
Arsène
A
Gaynor
Richard B
RB
Bex
Françoise
F
D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding; D021381:Protein Transport; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016356:Gene Products, tax; D016328:NF-kappa B; D025842:SUMO-1 Protein; D051996:Transcription Factor RelA; C107792:UBQLN1 protein, human; D051550:I-kappa B Kinase; D008239:Lysine