Journal article
Inhibitors of Tax1-PDZ Interactions Block HTLV-1 Viral Transmission by Changing EV Composition
Journal of extracellular vesicles, v 14(8), e70137
01 Aug 2025
PMID: 40767036
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.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.
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Details
- Title
- Inhibitors of Tax1-PDZ Interactions Block HTLV-1 Viral Transmission by Changing EV Composition
- Creators
- Jedidja Puttemans - University of LiègeYasmine Brammerloo - University of LiègeKarim Blibek - University of LiègeJeremy Blavier - University of LiègeThandokuhle Ntombela - University of LiègeInge Van Molle - VIB-VUB Center for Structural BiologyJulie Joseph - Drexel UniversityJulien Olivet - University of LiègeDeeya Saha - University of LiègeManon Degey - University of LiègeMalik Hamaidia - University of LiègePooja Jain - Drexel UniversityPiel GeraldinePascale Zimmermann - InsermDae-Kyum KimDominique Baiwir - University of LiègeMakon-Sébastien NjockFranck DequiedtKourosh Salehi-Ashtiani - New York UniversitySteven Ballet - Vrije Universiteit BrusselAlexander N Volkov - VIB-VUB Center for Structural BiologyJean-Claude TwizereSibusiso B Maseko - University of Liège
- Publication Details
- Journal of extracellular vesicles, v 14(8), e70137
- Publisher
- Wiley
- Number of pages
- 19
- Grant note
- FWO-FRS-FNRS: TW01423F FRS-FNRS Televie: 30823819 Fund for Research Training in Industry and Agriculture: 24343558 Funds Suzanne Dechesne, Serge Rousseau and Docteur Jean GeraldLa Ligue Nationale Contre le Cancer (Label 2018)Fund for Scientific Research Flanders (FWO): G0C5718N KU Leuven: C14/20/105 EDRFWalloon RegionNYUAD from the Division of Science (NYUAD, UAE): AD060
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 Qualifie 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.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology; Neurobiology and Anatomy
- Web of Science ID
- WOS:001544670700001
- Scopus ID
- 2-s2.0-105012613095
- Other Identifier
- 991022071576604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology