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

  1. Keisuke Tabata
  2. Vibhu Prasad
  3. David Paul
  4. Ji-Young Lee
  5. Minh-Tu Pham
  6. Woan-Ing Twu
  7. Christopher J. Neufeldt
  8. Mirko Cortese
  9. Berati Cerikan
  10. Yannick Stahl
  11. Sebastian Joecks
  12. Cong Si Tran
  13. Christian Lüchtenborg
  14. Philip V’kovski
  15. Katrin Hörmann
  16. André C. Müller
  17. Carolin Zitzmann
  18. Uta Haselmann
  19. Jürgen Beneke
  20. Lars Kaderali
  21. Holger Erfle
  22. Volker Thiel
  23. Volker Lohmann
  24. Giulio Superti-Furga
  25. Britta Brügger
  26. Ralf Bartenschlager

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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.

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  1. Version published to 10.1038/s41467-021-27511-1
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    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

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    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2021.05.10.443480v1 on bioRxiv