Dengue virus harnesses mosquito Syntenin to load and secrete viral RNA into salivary exosomes

Viruses exploit extracellular vesicles (EVs) to transfer infection-enhancing viral RNAs. However, mechanisms underlying viral RNA loading remain elusive. We leveraged our previous discovery that dengue virus secretes transmission-enhancing subgenomic flaviviral RNA (sfRNA) into mosquito salivary EVs to investigate viral RNA loading mechanism. We demonstrate that sfRNA alone promotes the secretion of sfRNA-containing EVs marked by the mosquito EV biogenesis protein AeSyntenin, by applying microscopy and viral genetic editing in in vitro and in vivo models. SfRNA via its stem loop structures interacts intracellularly with mosquito AeSyntenin and this interaction is selectively maintained within EVs as shown by complementary RNA-affinity chromatography and RNA immunoprecipitation, and AI-based prediction. Finally, we used systemic and salivary gland-specific protein depletion to establish a functional role for mosquito AeSyntenin in exosome production and salivary secretion of sfRNA. We propose that sfRNA binds AeSyntenin to drive its selective packaging and release into exosomes, elucidating a mechanism for viral RNA incorporation into EVs.

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Journal
Proceedings of the National Academy of Sciences
Published
2026-03-16
DOI
https://doi.org/10.1073/pnas.2520697123
Primary Topic
Extracellular vesicles in disease
Type
article
Field-Weighted Citation Impact
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article

Dengue virus harnesses mosquito Syntenin to load and secrete viral RNA into salivary exosomes

Sander Jansen, Audrey Vernet, Joséphine Lai‐Kee‐Him, Serge Urbach et al.
Proceedings of the National Academy of Sciences
Extracellular vesicles in disease
article

Dengue virus harnesses mosquito Syntenin to load and secrete viral RNA into salivary exosomes

Sander Jansen, Audrey Vernet, Joséphine Lai‐Kee‐Him, Serge Urbach, Idalba Serrato-Pomar, Jacques Dainat, Éric Marois, Martial Sevéno, Philippe Hammann, Elliott F. Miot, Julien Pompon, Florian Rachenne, Aurélie Ancelin, Marie Morille, Laurianne Simon, Félix Rey-Cadilhac, Lauryne Pruvost, Laura Di Pietro, Norman R. Schneider, Kai Dallmeier, Dorothée Missé, Chantal Cazevieille, Jérémy Fraering
article en

Abstract

Viruses exploit extracellular vesicles (EVs) to transfer infection-enhancing viral RNAs. However, mechanisms underlying viral RNA loading remain elusive. We leveraged our previous discovery that dengue virus secretes transmission-enhancing subgenomic flaviviral RNA (sfRNA) into mosquito salivary EVs to investigate viral RNA loading mechanism. We demonstrate that sfRNA alone promotes the secretion of sfRNA-containing EVs marked by the mosquito EV biogenesis protein AeSyntenin, by applying microscopy and viral genetic editing in in vitro and in vivo models. SfRNA via its stem loop structures interacts intracellularly with mosquito AeSyntenin and this interaction is selectively maintained within EVs as shown by complementary RNA-affinity chromatography and RNA immunoprecipitation, and AI-based prediction. Finally, we used systemic and salivary gland-specific protein depletion to establish a functional role for mosquito AeSyntenin in exosome production and salivary secretion of sfRNA. We propose that sfRNA binds AeSyntenin to drive its selective packaging and release into exosomes, elucidating a mechanism for viral RNA incorporation into EVs.

Proceedings of the National Academy of SciencesVol. 123(12)
École Nationale Supérieure de Chimie de Montpellier (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Montpellier (FR), Rega Institute for Medical Research (BE), Mahidol University (TH), Maladies Infectieuses et Vecteurs: Écologie, Génétique, Évolution et Contrôle (FR), New York Structural Biology Center (US), Institut de Biologie Moléculaire des Plantes (FR), Institut de Génétique Moléculaire de Montpellier (FR), Institut Charles Gerhardt Montpellier (FR), Institute for Neurosciences of Montpellier (FR), Services déconcentrés d'appui à la recherche Occitanie-Montpellier (FR), Institut de Génomique Fonctionnelle (FR), Institut de Biologie Moléculaire et Cellulaire (FR), Institut de Génétique Humaine (FR), Chiang Mai University (TH), Université de Strasbourg (FR)
Openalex Percentile: Top 21%
Extracellular vesicles in disease
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