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

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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.

    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.

     

    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.

    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