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    HTLV-1, regulation of virus expression and host cell modification


    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.

    HTLV-1, alike all other retroviruses, is able to integrate its reverse-transcribed genome within the host cell genome, generating thereby the proviral genome flanked by two non-coding LTR regions (Long Terminal Repeats at both the 5’ and 3’ ends), containing transcriptional regulatory elements. The HTLV-1 genome encodes for structural proteins and enzymes as well as for regulatory and auxiliary proteins. Among the latter, two products have been shown to promote T-cell proliferation: the regulatory protein Tax (TransActivator of pX) and the auxiliary protein HBZ (HTLV-1 Basic Zipper protein).


    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 different clinical forms of ATL.



    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.

    Marcais, A., Waast, L., Bruneau, J., Hanssens, K., Asnafi, V., Gaulard, P., Suarez, F., Dubreuil, P., Gessain, A., Hermine, O., Pique, C. (2017). Adult T cell leukemia aggressivenness correlates with loss of both 5-hydroxymethylcytosine and TET2 expression Oncotarget. 8(32):52256-68

    Groussaud, D., Khair, M., Tollenaere, A. I., Waast, L., Kuo, M. S., Mangeney, M., Martella, C., Fardini, Y., Coste, S., Souidi, M., Benit, L., Pique, C*., Issad, *T. (2017) Hijacking of the O-GlcNAcZYME complex by the HTLV-1 Tax oncoprotein facilitates viral transcription PLoS Pathog. 13(7):e1006518. * co-last authors