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

Author

Listed:
  • 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)
    Goethe University)

  • Paul Rothhaar

    (Medical Faculty)

  • Kyle J. Price

    (University of Wisconsin)

  • Thibault Tubiana

    (Institute for Integrative Biology of the Cell (I2BC))

  • Mathias Munschauer

    (Medical Faculty
    Helmholtz-Center for Infection Research (HZI)
    Goethe University)

  • David N. Frick

    (University of Wisconsin)

  • Volker Lohmann

    (Medical Faculty
    INF 344)

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.

Suggested Citation

  • Philipp Ralfs & Stéphane Bressanelli & Lina M. Günter & Alexander Gabel & Paul Rothhaar & Kyle J. Price & Thibault Tubiana & Mathias Munschauer & David N. Frick & Volker Lohmann, 2025. "Hepatitis C virus NS3 helicase contributes to (−) strand RNA synthesis," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63498-9
    DOI: 10.1038/s41467-025-63498-9
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