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    HTLV-1, Tax and T-cell Transformation

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    Team leader : Claudine PIQUE

     

    HTLV-1 belongs to the small group of viruses associated to a cancer in human. Indeed, this retrovirus is responsible for Adult T-cell leukemia (ATL), a malignant proliferation of CD4+ T cells. The transforming ability of HTLV-1 is mainly due to the production of the viral oncoprotein Tax that is able to alter a wide set of cellular pathways. Among them, permanent activation of the NF-kB pathway is a key event in the process of T-lymphocyte transformation. While the exact mechanism involved is still not completely identified, it has been shown that Tax recruits the IKKgamma component of the IkB kinase (IKK) complex, resulting in IKK activation, IkB degradation and nuclear translocation of kB factors.


    During the last decade, we have discovered that Tax does not exist as a single species in the cell but rather as a myriad of sub-populations, each characterized by a particular combination of post-translational modifications. In particular, we demonstrated that Tax is ubiquitinated, notably via conjugation to non-degradative ubiquitin chain, and that this event is essential for the activation of the NF-kB pathway. We have also demonstrated that Tax is sumoylated and that these modified populations are present in the nucleus. We are now studying the role of post-translational modifications of Tax during the T cell transformation process.

    More recently, we initiated new projects regarding the mechanisms by which HTLV-1 induces a transcriptional reprogramming of infected T lymphocytes. We studied in particular how the two HTLV-1 oncoproteins Tax and HBZ modulate DNA methylation and histone modifications and the link between these processes and the development of the diverses clinical forms of ATL.

     

    Publications:

     Chiari, E., Lamsoul, I., Chopin, C., Bex, F., and Pique, C.  (2004). A stable ubiquitination of the HTLV-1-Tax that is required for proteasome binding. J. Virol. 78: 18823-832.

     Nasr, R., Chiari, E., El-Sabban M., Mahieux, R., Kfoury, Y., Abdulay, M., Yazbeck, V., Hermine, O., deThé, H., Pique, C*. and Bazarbachi, A*. (2006). Tax ubiquitylation and sumoylation control critical cytoplasmic and nuclear steps of NF-kB activation. Blood. 107: 4021-4029. (* co-last authors)

    Chiari, E., Nasr, R., Favre-Bonvin, A., Kfoury, Y., Bazarbachi, A., et  Pique, C. 2007. L’oncoprotéine Tax du HTLV-1 dans la cellule : des manipulations réciproques. Virologie (Review). 11 : 1-11.

    Kfoury, Y., Nasr, R., Favre-Bonvin, A., El-Sabban, M., Renault, N., Giron, M.L., Setterblad, N., El Hajj, H., Chiari, E., Ghani Mikati, A., Hermine, O., Saib, A., de Thé, H., Pique, C., and Bazarbachi, A. (2008). Ubiquitylated Tax targets and binds the IKK signalosome at the centrosome. Oncogene. 27:1665-76.

    Kfoury, K., Setterblad, N., El-Sabban, M., Dassouki, Z., El Hajj, H., Hermine, O., Pique, C., de Thé, H., Saib, A., and Bazarbachi, A. (2011). Blood. Tax ubiquitylation and SUMOylation control the dynamic shuttling of Tax and NEMO between Ubc9 nuclear bodies and the centrosome. 117:190-9.

    Kfoury, Y., Nasr, R., Journo, C., Mahieux, R., Pique, C., and Bazarbachi, A. (2012). The multifaceted oncoprotein Tax: Sub-cellular localization, post-translational modifications and NF-κB activation. Adv. Cancer Res. 113:85-120. (Review).

    Bonnet, A., Randrianarison-Huetz, V, Nzounza, P., Favre-Bonvin, A., Pene, S., Nedelec, M., Chazal, M., Waast, L., Bazarbachi, A., Mahieux, R., Bénit, L., and Pique, C. (2012). Low SUMOylation and nuclear body formation do not prevent Tax-induced NF-kB promoter activation in primary or HTLV-1-infected T cells. Retrovirology. 25;9:77.

    Journo, C., Bonnet, A., Favre-Bonvin, A., Turpin, J., Vinera, J., Côté, E., Chevalier, S.A., Pique, C* and Mahieux, R*. (2013). HTLV-2 Tax mediated NF-kB activation involves a mechanisms independent of Tax conjugation to ubiquitin and SUMO. J. Virol. 87(2):1123-36. * co-last authors

    Pene, S., Waast, L., Bonnet, A., Bénit, L., and Pique, C. (2014). A non-Sumoylated Tax is still functional for NF-kB pathway activation. J. Virol. 88(18):10655. DOI: 10.1128/JVI.01827-14.