Inhibitors of Tax1‐PDZ Interactions Block HTLV‐1 Viral Transmission by Changing EV Composition
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.
Authors
- Steven Ballet (ORCID: https://orcid.org/0000-0003-4123-1641)
- Deeya Saha
- Sibusiso B. Maseko
- Thandokuhle Ntombela (ORCID: https://orcid.org/0000-0003-0295-7546)
- Pascale Zimmermann (ORCID: https://orcid.org/0000-0001-8768-1790)
- Pooja Jain (ORCID: https://orcid.org/0000-0002-9925-4259)
- Malik Hamaïdia (ORCID: https://orcid.org/0000-0003-0459-4005)
- Karim Blibek
- Julien Olivet (ORCID: https://orcid.org/0000-0003-4115-5546)
- Makon‐Sébastien Njock (ORCID: https://orcid.org/0000-0001-8137-1978)
- Kourosh Salehi‐Ashtiani (ORCID: https://orcid.org/0000-0002-6521-5243)
- Yasmine Brammerloo (ORCID: https://orcid.org/0009-0004-0295-5297)
- Samuel Dequiedt (ORCID: https://orcid.org/0000-0003-1234-7477)
- Jérémy Blavier (ORCID: https://orcid.org/0000-0002-7055-6907)
- Dae‐Kyum Kim (ORCID: https://orcid.org/0000-0003-4568-8278)
- Dominique Baiwir (ORCID: https://orcid.org/0000-0002-1622-0118)
- Julie Joseph (ORCID: https://orcid.org/0000-0002-6920-0364)
- Jean‐Claude Twizere (ORCID: https://orcid.org/0000-0002-8683-705X)
- Manon Degey
- Géraldine Piel (ORCID: https://orcid.org/0000-0001-8632-4492)
- Inge Van Molle (ORCID: https://orcid.org/0000-0003-0114-9379)
- Alexander N. Volkov (ORCID: https://orcid.org/0000-0002-5184-986X)
- Jedidja Puttemans
Institutions
- New York University Abu Dhabi (AE)
- Centre National de la Recherche Scientifique (FR)
- Vrije Universiteit Brussel (BE)
- Inserm (FR)
- University of Liège (BE)
- Rega Institute for Medical Research (BE)
- Gembloux Agro-Bio Tech (BE)
- Montreal General Hospital (CA)
- McGill University Health Centre (CA)
- M S Ramaiah University of Applied Sciences (IN)
- VIB-VUB Center for Structural Biology (BE)
- Centre de Recherche en Cancérologie de Marseille (FR)
- McGill University (CA)
- Drexel University (US)
- KU Leuven (BE)
Publication Details
- Journal
- Journal of Extracellular Vesicles
- Published
- 2025-08-01
- DOI
- https://doi.org/10.1002/jev2.70137
- Citations
- 2
- Primary Topic
- T-cell and Retrovirus Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.59
Funders
- New York University Abu Dhabi
- Fonds De La Recherche Scientifique - FNRS
- Fonds Wetenschappelijk Onderzoek
- KU Leuven
- Ligue Contre le Cancer
- Vlaamse regering