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High levels of cytoplasmic HTLV-1 Tax mutant proteins retain a Tax-NF-κB-CBP ternary complex in the cytoplasm

Abstract

The oncogenic potential of HTLV-1 Tax protein is partially ascribed to its capacity to activate NF-κB. The current view is that Tax acts first in the cytoplasm to dissociate NF-κB factors from the IκB proteins and enable their nuclear translocation, then Tax links p65(RelA), within the nucleus, to CBP/p300 and P/CAF, which are essential for its optimal transcriptional activity. Our present study challenges the paradigm that Tax–p65(RelA)-CBP/p300 assembly occurs in the nucleus. Using Tax mutants defective for nuclear localization we show that at low levels these mutants induce the nuclear translocation of NF-κB factors but not their transcriptional activity, whereas at high levels they trap CBP and free p65(RelA) in the cytoplasm and block, thereby, their transcriptional function. In contrast, wild-type (w.t.) Tax strongly stimulated NF-κB-dependent gene expression in all tested experimental settings. These data suggest that the Tax–p65(RelA)-CBP ternary complex is established in the cytoplasm rather than in the nucleus. When this complex is formed with w.t. Tax, the entire moiety translocates into the nucleus and exerts high transcriptional activity. However, if the complex is formed with the cytoplasmic Tax mutants, the resulting moiety is retained in the cytoplasm and is, therefore, devoid of transcriptional activity.

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Acknowledgements

This study was supported by grants from the Israel Science Foundation of the Israeli National Academy of Sciences and Humanities, from the Joint Cancer Research Program of the Israeli Ministry of Sciences (MOS) and the German Cancer Research Center (DKFZ) and from The Chief Scientist Office of the Israeli Health Ministry.

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Correspondence to Mordechai Aboud.

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Azran, I., Jeang, KT. & Aboud, M. High levels of cytoplasmic HTLV-1 Tax mutant proteins retain a Tax-NF-κB-CBP ternary complex in the cytoplasm. Oncogene 24, 4521–4530 (2005). https://doi.org/10.1038/sj.onc.1208645

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