PT  - JOURNAL ARTICLE
AU  - Sibusiso B. Maseko
AU  - Inge Van Molle
AU  - Karim Blibek
AU  - Christoph Gorgulla
AU  - Julien Olivet
AU  - Jeremy Blavier
AU  - Charlotte Vandermeulen
AU  - Stéphanie Skupiewski
AU  - Deeya Saha
AU  - Thandokuhle Ntombela
AU  - Julianne Lim
AU  - Frederique Lembo
AU  - Aurelie Beauvois
AU  - Malik Hamaidia
AU  - Jean-Paul Borg
AU  - Pascale Zimmermann
AU  - Frank Delvigne
AU  - Luc Willems
AU  - Johan Van Weyenbergh
AU  - Dae-Kyum Kim
AU  - Franck Dequiedt
AU  - Haribabu Arthanari
AU  - Kourosh Salehi-Ashtiani
AU  - Steven Ballet
AU  - Alexander N. Volkov
AU  - Jean-Claude Twizere
TI  - Structural basis for targeting the human T-cell leukemia virus Tax oncoprotein and syntenin-1 interaction using a small molecule
AID  - 10.1101/2021.08.25.457680
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2021.08.25.457680
4099  - http://biorxiv.org/content/early/2022/03/18/2021.08.25.457680.short
4100  - http://biorxiv.org/content/early/2022/03/18/2021.08.25.457680.full
AB  - 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.Competing Interest StatementThe authors have declared no competing interest.