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Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation

Author

Listed:
  • Keisuke Tabata

    (Heidelberg University
    Osaka University
    Osaka University)

  • Vibhu Prasad

    (Heidelberg University)

  • David Paul

    (Heidelberg University
    MRC Laboratory of Molecular Biology)

  • Ji-Young Lee

    (Heidelberg University)

  • Minh-Tu Pham

    (Heidelberg University)

  • Woan-Ing Twu

    (Heidelberg University)

  • Christopher J. Neufeldt

    (Heidelberg University)

  • Mirko Cortese

    (Heidelberg University)

  • Berati Cerikan

    (Heidelberg University)

  • Yannick Stahl

    (Heidelberg University)

  • Sebastian Joecks

    (Heidelberg University
    LI-COR Biosciences GmbH)

  • Cong Si Tran

    (Heidelberg University)

  • Christian Lüchtenborg

    (Heidelberg University)

  • Philip V’kovski

    (Institute of Virology and Immunology IVI
    University of Bern)

  • Katrin Hörmann

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • André C. Müller

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences)

  • Carolin Zitzmann

    (University Medicine Greifswald
    Theoretical Biology and Biophysics)

  • Uta Haselmann

    (Heidelberg University)

  • Jürgen Beneke

    (Heidelberg University)

  • Lars Kaderali

    (University Medicine Greifswald)

  • Holger Erfle

    (Heidelberg University)

  • Volker Thiel

    (Institute of Virology and Immunology IVI
    University of Bern)

  • Volker Lohmann

    (Heidelberg University)

  • Giulio Superti-Furga

    (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
    Medical University of Vienna)

  • Britta Brügger

    (Heidelberg University)

  • Ralf Bartenschlager

    (Heidelberg University
    German Cancer Research Center
    Heidelberg Partner Site)

Abstract

Double membrane vesicles (DMVs) serve as replication organelles of plus-strand RNA viruses such as hepatitis C virus (HCV) and SARS-CoV-2. Viral DMVs are morphologically analogous to DMVs formed during autophagy, but lipids driving their biogenesis are largely unknown. Here we show that production of the lipid phosphatidic acid (PA) by acylglycerolphosphate acyltransferase (AGPAT) 1 and 2 in the ER is important for DMV biogenesis in viral replication and autophagy. Using DMVs in HCV-replicating cells as model, we found that AGPATs are recruited to and critically contribute to HCV and SARS-CoV-2 replication and proper DMV formation. An intracellular PA sensor accumulated at viral DMV formation sites, consistent with elevated levels of PA in fractions of purified DMVs analyzed by lipidomics. Apart from AGPATs, PA is generated by alternative pathways and their pharmacological inhibition also impaired HCV and SARS-CoV-2 replication as well as formation of autophagosome-like DMVs. These data identify PA as host cell lipid involved in proper replication organelle formation by HCV and SARS-CoV-2, two phylogenetically disparate viruses causing very different diseases, i.e. chronic liver disease and COVID-19, respectively. Host-targeting therapy aiming at PA synthesis pathways might be suitable to attenuate replication of these viruses.

Suggested Citation

  • Keisuke Tabata & Vibhu Prasad & David Paul & Ji-Young Lee & Minh-Tu Pham & Woan-Ing Twu & Christopher J. Neufeldt & Mirko Cortese & Berati Cerikan & Yannick Stahl & Sebastian Joecks & Cong Si Tran & C, 2021. "Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27511-1
    DOI: 10.1038/s41467-021-27511-1
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    References listed on IDEAS

    as
    1. Petter Holland & Helene Knævelsrud & Kristiane Søreng & Benan J. Mathai & Alf Håkon Lystad & Serhiy Pankiv & Gunnveig T. Bjørndal & Sebastian W. Schultz & Viola H. Lobert & Robin B. Chan & Bowen Zhou , 2016. "HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    2. Steffen Klein & Mirko Cortese & Sophie L. Winter & Moritz Wachsmuth-Melm & Christopher J. Neufeldt & Berati Cerikan & Megan L. Stanifer & Steeve Boulant & Ralf Bartenschlager & Petr Chlanda, 2020. "SARS-CoV-2 structure and replication characterized by in situ cryo-electron tomography," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    3. Alessandro Pagliuso & Carmen Valente & Lucia Laura Giordano & Angela Filograna & Guiling Li & Diego Circolo & Gabriele Turacchio & Vincenzo Manuel Marzullo & Luigi Mandrich & Mikhail A. Zhukovsky & Fa, 2016. "Golgi membrane fission requires the CtBP1-S/BARS-induced activation of lysophosphatidic acid acyltransferase δ," Nature Communications, Nature, vol. 7(1), pages 1-15, November.
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    3. Nell Saunders & Blandine Monel & Nadège Cayet & Lorenzo Archetti & Hugo Moreno & Alexandre Jeanne & Agathe Marguier & Julian Buchrieser & Timothy Wai & Olivier Schwartz & Mathieu Fréchin, 2024. "Dynamic label-free analysis of SARS-CoV-2 infection reveals virus-induced subcellular remodeling," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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