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

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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Philipp Ralfs: Medical Faculty
Stéphane Bressanelli: Institute for Integrative Biology of the Cell (I2BC)
Lina M. Günter: Helmholtz-Center for Infection Research (HZI)
Alexander Gabel: Helmholtz-Center for Infection Research (HZI)
Paul Rothhaar: Medical Faculty
Kyle J. Price: University of Wisconsin
Thibault Tubiana: Institute for Integrative Biology of the Cell (I2BC)
Mathias Munschauer: Medical Faculty
David N. Frick: University of Wisconsin
Volker Lohmann: Medical Faculty

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63498-9

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