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

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, Christian Lüchtenborg, Philip V’kovski, Katrin Hörmann, André C. Müller, Carolin Zitzmann, Uta Haselmann, Jürgen Beneke, Lars Kaderali, Holger Erfle, Volker Thiel, Volker Lohmann, Giulio Superti-Furga, Britta Brügger and Ralf Bartenschlager ()
Additional contact information
Keisuke Tabata: Heidelberg University
Vibhu Prasad: Heidelberg University
David Paul: Heidelberg University
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
Cong Si Tran: Heidelberg University
Christian Lüchtenborg: Heidelberg University
Philip V’kovski: Institute of Virology and Immunology IVI
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
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
Volker Lohmann: Heidelberg University
Giulio Superti-Furga: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Britta Brügger: Heidelberg University
Ralf Bartenschlager: Heidelberg University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27511-1

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