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SQSTM-1/p62 potentiates HTLV-1 Tax-mediated NF-kappa B activation through its ubiquitin binding function

Schwob, A., Teruel, E., Dubuisson, L., Lormieres, F., Verlhac, P., Abudu, Y. P., Gauthier, J., Naoumenko, M., Cloarec-Ung, F-M., Faure, M., Johansen, T., Dutartre, H., Mahieux, R. & Journo, C., 5-Nov-2019, In : Scientific Reports. 9, 17 p., 16014.

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  • Aurelien Schwob
  • Elodie Teruel
  • Louise Dubuisson
  • Florence Lormieres
  • Pauline Verlhac
  • Yakubu Princely Abudu
  • Janelle Gauthier
  • Marie Naoumenko
  • Fanny-Mei Cloarec-Ung
  • Mathias Faure
  • Terje Johansen
  • Helene Dutartre
  • Renaud Mahieux
  • Chloe Journo

The NF-kappa B pathway is constitutively activated in adult T cell leukemia, an aggressive malignancy caused by Human T Leukemia Virus type 1 (HTLV-1). The viral oncoprotein Tax triggers this constitutive activation by interacting with the ubiquitin-rich IKK complex. We previously demonstrated that Optineurin and TAX1BP1, two members of the ubiquitin-binding, Sequestosome-1 (SQSTM-1/p62)like selective autophagy receptor family, are involved in Tax-mediated NF-kappa B signaling. Here, using a proximity-dependent biotinylation approach (BioID), we identify p62 as a new candidate partner of Tax and confirm the interaction in infected T cells. We then demonstrate that p62 knock-out in MEF cells as well as p62 knock-down in HEK293T cells significantly reduces Tax-mediated NF-kappa B activity. We further show that although p62 knock-down does not alter NF-kappa B activation in Jurkat T cells nor in infected T cells, p62 does potentiate Tax-mediated NF-kappa B activity upon over-expression in Jurkat T cells. We next show that p62 associates with the Tax/IKK signalosome in cells, and identify the 170-206 domain of p62 as sufficient for the direct, ubiquitin-independent interaction with Tax. However, we observe that this domain is dispensable for modulating Tax activity in cells, and functional analysis of p62 mutants indicates that p62 could potentiate Tax activity in cells by facilitating the association of ubiquitin chains with the Tax/IKK signalosome. Altogether, our results identify p62 as a new ubiquitin-dependent modulator of Tax activity on NF-kappa B, further highlighting the importance of ubiquitin in the signaling activity of the viral Tax oncoprotein.

Original languageEnglish
Article number16014
Number of pages17
JournalScientific Reports
Volume9
Publication statusPublished - 5-Nov-2019

    Keywords

  • T-CELL LEUKEMIA, VIRUS TYPE-1 TAX, KINASE IKK, AUTOPHAGY, PROTEIN, P62, ONCOPROTEIN, P62/SQSTM1, INFECTION, DOMAIN

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