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Hepatitis C virus NS3 helicase contributes to (−) strand RNA synthesis

Many positive strand RNA viruses encode helicases, but their distinct functions in viral replication cycles is poorly understood. Here, we identify a mutation in the helicase domain of HCV non-structural protein 3 (NS3h), D1467G, which specifically affects (−) strand synthesis, phenocopying mutation...

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Main Authors: Ralfs, Philipp (Author) , Bressanelli, Stéphane (Author) , Günter, Lina M. (Author) , Gabel, Alexander (Author) , Rothhaar, Paul (Author) , Price, Kyle J. (Author) , Tubiana, Thibault (Author) , Munschauer, Mathias (Author) , Frick, David N. (Author) , Lohmann, Volker (Author)
Format: Article (Journal)
Language:English
Published: 27 August 2025
In: Nature Communications
Year: 2025, Volume: 16, Pages: 1-21
ISSN:2041-1723
DOI:10.1038/s41467-025-63498-9
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-63498-9
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-63498-9
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Author Notes:Philipp Ralfs, Stéphane Bressanelli, Lina M. Günter, Alexander Gabel, Paul Rothhaar, Kyle J. Price, Thibault Tubiana, Mathias Munschauer, David N. Frick, and Volker Lohmann
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Summary:Many positive strand RNA viruses encode helicases, but their distinct functions in viral replication cycles is poorly understood. Here, we identify a mutation in the helicase domain of HCV non-structural protein 3 (NS3h), D1467G, which specifically affects (−) strand synthesis, phenocopying mutations in the 3’ untranslated region of the genome. D1467G does not impair helicase activity in vitro or the binding of NS3h to critical cis-acting RNA elements, but reduces the interaction of NS3h and NS5B polymerase, potentially contributing to defective (−) strand synthesis. AlphaFold predictions of complexes between NS3h, RNA and/or NS5B suggest that NS3h both remodels the cis-acting RNA elements and unwinds the terminal stem-loop of the HCV genome rendering the template accessible for de novo initiation of (−) strand synthesis by NS5B. Overall, our study provides evidence for a defined function of a viral helicase in (−) strand genome synthesis of a positive strand RNA virus.
Item Description:Gesehen am 03.02.2026
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-025-63498-9

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