{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:20:10Z","timestamp":1790252410025,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,13]],"date-time":"2025-09-13T00:00:00Z","timestamp":1757721600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Natural Sciences and Engineering Research Council of Canada (NSERC)","award":["RGPIN-2021-03548"],"award-info":[{"award-number":["RGPIN-2021-03548"]}]},{"name":"Natural Sciences and Engineering Research Council of Canada (NSERC)","award":["DGECR-2021-00398"],"award-info":[{"award-number":["DGECR-2021-00398"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>The dengue virus (DENV) exploits host cell exosome pathways to disseminate and evade immunity. However, the host factors enabling this process remain poorly defined. Here, we demonstrate that DENV infection robustly induces expression of the short isoform of Reticulon 3 (RTN3S) in hepatic (Huh7) and monocytic cells, and that RTN3S is a critical driver of infectious exosome biogenesis. RTN3S physically associates with double-stranded viral RNA and the DENV non-structural protein 3 (NS3) in infected cells, indicating its integration into the viral replication complex. Loss of RTN3 markedly reduced exosome production and the exosomal export of viral RNA and proteins, demonstrating that RTN3S is required for efficient exosome-mediated viral release. Conversely, overexpression of full-length RTN3S dramatically increased the release of infectious virus-containing exosomes; truncation of the RTN3S C-terminal domain abolished this enhancement, confirming the essential role of the C-terminus in RTN3S\u2019s pro-viral exosomal function. In DENV-infected monocytes, we observed a shift toward a CD16-positive intermediate phenotype, accompanied by the upregulation of genes involved in vesicle biogenesis and stress response. These infected monocytes also secreted higher levels of inflammatory cytokines. Similarly, monocytes from Dengue patients exhibited high RTN3 expression, which correlated with an expansion of intermediate (CD16+) subsets and enriched expression of vesicle trafficking machinery genes. These findings reveal a previously unrecognized mechanism by which DENV hijacks RTN3S to promote the formation of infectious exosomes, thereby facilitating viral dissemination and immune evasion. RTN3S thus represents a novel element of the Dengue pathogenesis and a potential target for host-directed antiviral strategies.<\/jats:p>","DOI":"10.3390\/v17091238","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T07:56:51Z","timestamp":1757923011000},"page":"1238","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Integrative Mechanistic Studies Identify Reticulon-3 as a Critical Modulator of Infectious Exosome-Driven Dengue Pathogenesis"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-8343-8685","authenticated-orcid":false,"given":"Razieh","family":"Bitazar","sequence":"first","affiliation":[{"name":"Armand-Frappier Sant\u00e9 Biotechnologie Research Center, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"},{"name":"PROTEO, The Quebec Network for Research on Protein Function, Structure, and Engineering, Montr\u00e9al, QC H2X 3Y7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8371-9138","authenticated-orcid":false,"given":"Clinton Njinju","family":"Asaba","sequence":"additional","affiliation":[{"name":"Armand-Frappier Sant\u00e9 Biotechnologie Research Center, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saina","family":"Shegefti","sequence":"additional","affiliation":[{"name":"Armand-Frappier Sant\u00e9 Biotechnologie Research Center, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4145-029X","authenticated-orcid":false,"given":"Tatiana","family":"Noumi","sequence":"additional","affiliation":[{"name":"Armand-Frappier Sant\u00e9 Biotechnologie Research Center, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Van Grevenynghe","sequence":"additional","affiliation":[{"name":"Armand-Frappier Sant\u00e9 Biotechnologie Research Center, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6853-8446","authenticated-orcid":false,"given":"Salim T.","family":"Islam","sequence":"additional","affiliation":[{"name":"Armand-Frappier Sant\u00e9 Biotechnologie Research Center, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"},{"name":"PROTEO, The Quebec Network for Research on Protein Function, Structure, and Engineering, Montr\u00e9al, QC H2X 3Y7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Labont\u00e9","sequence":"additional","affiliation":[{"name":"Armand-Frappier Sant\u00e9 Biotechnologie Research Center, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3898-0617","authenticated-orcid":false,"given":"Terence Ndonyi","family":"Bukong","sequence":"additional","affiliation":[{"name":"Armand-Frappier Sant\u00e9 Biotechnologie Research Center, Institut National de la Recherche Scientifique, Laval, QC H7V 1B7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e620","DOI":"10.1016\/S1473-3099(24)00609-1","article-title":"Global upsurge in dengue in 2024","volume":"24","author":"Venkatesan","year":"2024","journal-title":"Lancet Infect. 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