2. Academic Validation
  3. Inhibitors of Tax1-PDZ Interactions Block HTLV-1 Viral Transmission by Changing EV Composition

Inhibitors of Tax1-PDZ Interactions Block HTLV-1 Viral Transmission by Changing EV Composition

  • J Extracell Vesicles. 2025 Aug;14(8):e70137. doi: 10.1002/jev2.70137.
Jedidja Puttemans 1,  Yasmine Brammerloo 1,  Karim Blibek 1,  Jeremy Blavier 1,  Thandokuhle Ntombela 1,  Inge Van Molle 2,  Julie Joseph 3,  Julien Olivet 1 4,  Deeya Saha 1 5,  Manon Degey 6,  Malik Hamaidia 7,  Pooja Jain 3,  Piel Geraldine 6,  Pascale Zimmermann 8 9,  Dae-Kyum Kim 10 11 12,  Dominique Baiwir 13,  Makon-Sébastien Njock 14,  Franck Dequiedt 15,  Kourosh Salehi-Ashtiani 16,  Steven Ballet 17,  Alexander N Volkov 2 18,  Jean-Claude Twizere 1 16 19,  Sibusiso B Maseko 1
Affiliations

Affiliations

  • 1 Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute, University of Liege, Liège, Belgium.
  • 2 VIB-VUB Center for Structural Biology, Flemish Institute of Biotechnology (VIB), Pleinlaan 2, Brussels, Belgium.
  • 3 Department of Microbiology & Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA.
  • 4 Structural Biology Lab, Molecular Structural & Translational Virology Group, Rega Institute for Medical Research and Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
  • 5 Dept. Of Biotechnology, Faculty of Life and Allied Health Sciences (FLAHS), M.S Ramaiah University of Applied Sciences (MSRUAS), Bangalore, India.
  • 6 Laboratoire de Technologie Pharmaceutique & Biopharmacie (LTPB), CIRM, University of Liège, Liège, Belgium.
  • 7 Laboratory of Cellular and Molecular Epigenetics, Cancer Unit, GIGA Institute, University of Liège, Liège, Belgium.
  • 8 Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe labellisée Ligue Cell polarity, Cell signaling and Cancer, Marseille, France.
  • 9 Department of Human Genetics, KU Leuven, Leuven, Belgium.
  • 10 Division of Thoracic and Upper Gastrointestinal Surgery, Department of Surgery, Faculty of Medicine and Health Sciences, McGill University, Montreal, Canada.
  • 11 Cancer Research Program, Research Institute of McGill University Health Centre, Montreal, Canada.
  • 12 Montreal General Hospital Foundation, McGill University Health Centre, Montreal, Canada.
  • 13 GIGA proteomics platform, University of Liège, Liège, Belgium.
  • 14 Laboratory of Pneumology, GIGA Institute, University of Liège, Liège, Belgium.
  • 15 Laboratory of Gene Expression and Cancer, Molecular Biology of Diseases Unit, GIGA Institute, University of Liège, Liège, Belgium.
  • 16 Division of Science and Math, New York University Abu Dhabi, Abu Dhabi, UAE.
  • 17 Research Group of Organic Chemistry, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
  • 18 Jean Jeener NMR Centre, Vrije Universiteit Brussel (VUB), Pleinlaan 2, Brussels, Belgium.
  • 19 TERRA research and teaching centre, Microbial Processes and Interactions (MiPI), Gembloux Agro Bio-tech, University of Liège, Gembloux, Belgium.
PMID: 40767036 DOI: 10.1002/jev2.70137
Abstract

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.

Keywords

PDZ; Tax‐1; interactome; miRNA; syntenin‐1.

Figures
Products