Interactome and structural basis for targeting the human T-cell leukemia virus Tax oncoprotein

Maseko, S.; Van Molle, I.; Blibek, K.; Gorgulla, C.; Olivet, J.; Blavier, J.; Vandermeulen, C.; Skupiewski, S.; Saha, D.; Ntombela, T.; Lim, J.; Lembo, F.; Beauvois, A.; Hamaidia, M.; Borg, J.-P.; Zimmermann, P.; Delvigne, F.; Willems, L.; Van Weyenbergh, J.; Kim, D.-K.; Dequiedt, F.; Arthanari, H.; Volkov, A.; Twizere, J.-C.

doi:10.1101/2021.08.25.457680

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bioRxiv · 10.1101/2021.08.25.457680

Interactome and structural basis for targeting the human T-cell leukemia virus Tax oncoprotein

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Abstract

Human T-cell leukemia virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). Although ATL is a well-characterized T-cell neoplasm, linked to intermittent expression of the viral Tax-1 protein, there is currently no strategy to target Tax-1 functions using small molecules. Here, we report a comprehensive interaction map between Tax-1 and human PDZ domain-containing proteins (hPDZome). We show that Tax-1 interacts with more than one-third of hPDZome components, including proteins involved in cell cycle, cell-cell junctions, cytoskeleton organization, and membrane complex assembly. Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the structural basis of the interaction between the C-terminal PDZ binding motif (PBM) of Tax-1, and the PDZ domains of syntenin-1, an evolutionary conserved hub that controls exosome trafficking. Finally, we have used confocal imaging, molecular modelling, NMR and mammalian cell-based assays to demonstrate that the Tax-1/syntenin-1 interaction is amenable to small-molecule inhibition. Altogether, our study highlights the biological significance of Tax-PDZ interactome and its interplay with exosome formation. It shows a direct link between extracellular vesicles and HTLV-1 transmission, providing a novel framework for the design of targeted therapies for HTLV-1-induced diseases.

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Maseko, S., Van Molle, I., Blibek, K., Gorgulla, C., Olivet, J., Blavier, J., Vandermeulen, C., Skupiewski, S., Saha, D., Ntombela, T., Lim, J., Lembo, F., Beauvois, A., Hamaidia, M., Borg, J.-P., Zimmermann, P., Delvigne, F., Willems, L., Van Weyenbergh, J., Kim, D.-K., Dequiedt, F., Arthanari, H., Volkov, A., Twizere, J.-C.. 2021-08-25. Interactome and structural basis for targeting the human T-cell leukemia virus Tax oncoprotein. https://doi.org/10.1101/2021.08.25.457680

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