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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| Hauptverfasser: | , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
27 August 2025
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| In: |
Nature Communications
Year: 2025, Jahrgang: 16, Pages: 1-21 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-025-63498-9 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 520 | |a 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. | ||
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