[en] Extracellular vesicles (EVs) are known to facilitate infection by enveloped RNA viruses including the Human T-cell leukemia virus type-1 (HTLV-1). HTLV-1-encoded proteins, like the transactivator and oncoprotein Tax-1, are loaded into EVs but their precise impact on EV cargos is not yet known. Here, we report a comprehensive interaction map between Tax-1 and the human PDZ (PSD95/DLG/ZO-1) proteins that regulate EVs formation and composition. 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. We extensively characterized Tax-1 interaction with syntenin-1, an evolutionary conserved PDZ hub that controls EV biogenesis. Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the structural basis of the interaction between the C-terminal PDZ binding motif of Tax-1, and two PDZ domains of syntenin-1. Importantly, we show that a small molecule able to inhibit HTLV-1 cell-to-cell transmission breaks the Tax-1/syntenin-1 interaction, impacts the levels of syntenin-1 and viral proteins in EVs, and shifts the EV composition toward cellular antiviral proteins and microRNAs, including the miR-320 family. Consequently, we demonstrate that mimics of miR-320c, encapsulated into EVs, have antiviral activities with a potential to be used against HTLV-1 induced diseases.
Ntombela, Thandokuhle ; Université de Liège - ULiège > Département GxABT > Microbial technologies
Van Molle, Inge; VIB-VUB Center for Structural Biology, Flemish Institute of Biotechnology (VIB), Pleinlaan 2, Brussels, Belgium
Joseph, Julie; Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
Olivet, Julien ; Université de Liège - ULiège > GIGA > GIGA Molecular & Computational Biology - Viral Interactomes Network ; Structural Biology Lab, Molecular Structural & Translational Virology Group, Rega Institute for Medical Research and Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
Saha, Deeya ; Université de Liège - ULiège > Agronomie, Bio-ingénierie et Chimie (AgroBioChem) > Microbial technologies ; Dept. Of Biotechnology, Faculty of Life and Allied Health Sciences (FLAHS), M.S Ramaiah University of Applied Sciences (MSRUAS), Bangalore, India
Degey, Manon ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Hamaïdia, Malik ; Université de Liège - ULiège > Département GxABT > Microbial technologies
Jain, Pooja ; Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
Geraldine, Piel; Laboratoire de Technologie Pharmaceutique & Biopharmacie (LTPB), CIRM, University of Liège, Liège, Belgium
Zimmermann, Pascale ; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe labellisée Ligue Cell polarity, Cell signaling and Cancer, Marseille, France ; Department of Human Genetics, KU Leuven, Leuven, Belgium
Kim, Dae-Kyum; Division of Thoracic and Upper Gastrointestinal Surgery, Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada ; Cancer Research Program, Research Institute of McGill University Health Centre, Montreal, Canada ; Montreal General Hospital Foundation, McGill University Health Centre, Montreal, Canada
Baiwir, Dominique ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Dequiedt, Franck ; Université de Liège - ULiège > Département des sciences de la vie > Génétique et biologie moléculaires animales
Salehi-Ashtiani, Kourosh; Division of Science and Math, New York University Abu Dhabi, Abu Dhabi, UAE
Ballet, Steven; Research Group of Organic Chemistry, Vrije Universiteit Brussel (VUB), Brussels, Belgium
Volkov, Alexander N; VIB-VUB Center for Structural Biology, Flemish Institute of Biotechnology (VIB), Pleinlaan 2, Brussels, Belgium ; Jean Jeener NMR Centre, Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussels, Belgium
Twizere, Jean-Claude ✱; Université de Liège - ULiège > GIGA > GIGA Molecular & Computational Biology - Viral Interactomes Network ; Division of Science and Math, New York University Abu Dhabi, Abu Dhabi, UAE
This work was primarily supported by the FWO-FRS-FNRS Weave grant TW01423F to Steven Ballet, Jean-Claude Twizere and Alexander N. Volkov, FRS-FNRS Televie grants 30823819 to Jean-Claude Twizere; Fund for Research Training in Industry and Agriculture grant 24343558 to Karim Blibek. Franck Dequiedt is a Chercheur Qualifi\u00E9 Honoraire, Jean-Claude Twizere a Research Director, Sibusiso B. Maseko is a postdoctoral fellow of the F.R.S.-FNRS. Sibusiso B. Maseko is further supported by the Funds Suzanne Dechesne, Serge Rousseau and Docteur Jean Gerald, Managed by King Boudouin Foundation. Pascale Zimmermann's lab work was funded by La Ligue Nationale Contre le Cancer (Label 2018), the Fund for Scientific Research Flanders (FWO, G0C5718N) and the internal funds of the KU Leuven (C14/20/105). Q Exactive mass spectrometer (GIGA Proteomics Facility) was acquired thanks to EDRF and Walloon Region funding. This research was also supported by NYUAD Faculty Research Funds (AD060) from the Division of Science (NYUAD, UAE) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Computational resources have been provided by the Consortium des \u00C9quipements de Calcul Intensif (C\u00C9CI), funded by the Fonds de la Recherche Scientifique (FRS-FNRS, Belgium) under Grant No. 2.5020.11 and by the Walloon Region. We thank the Genomics, Bioinformatics, Proteomics and Viral Vectors core facilities of the University of Liege for their services.Computational resources have been provided by the Consortium des \u00C9quipements de Calcul Intensif (C\u00C9CI), funded by the Fonds de la Recherche Scientifique (FRS\u2010FNRS, Belgium) under Grant No. 2.5020.11 and by the Walloon Region. We thank the Genomics, Bioinformatics, Proteomics and Viral Vectors core facilities of the University of Liege for their services.: This work was primarily supported by the FWO\u2010FRS\u2010FNRS Weave grant TW01423F to Steven Ballet, Jean\u2010Claude Twizere and Alexander N. Volkov, FRS\u2010FNRS Televie grants 30823819 to Jean\u2010Claude Twizere; Fund for Research Training in Industry and Agriculture grant 24343558 to Karim Blibek. Franck Dequiedt is a Chercheur Qualifi\u00E9 Honoraire, Jean\u2010Claude Twizere a Research Director, Sibusiso B. Maseko is a postdoctoral fellow of the F.R.S.\u2010FNRS. Sibusiso B. Maseko is further supported by the Funds Suzanne Dechesne, Serge Rousseau and Docteur Jean Gerald, Managed by King Boudouin Foundation. Pascale Zimmermann's lab work was funded by La Ligue Nationale Contre le Cancer (Label 2018), the Fund for Scientific Research Flanders (FWO, G0C5718N) and the internal funds of the KU Leuven (C14/20/105). Q Exactive mass spectrometer (GIGA Proteomics Facility) was acquired thanks to EDRF and Walloon Region funding. This research was also supported by NYUAD Faculty Research Funds (AD060) from the Division of Science (NYUAD, UAE) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding
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