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

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 o...

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Main Authors: Tabata, Keisuke (Author) , Prasad, Vibhu (Author) , Paul, David (Author) , Lee, Ji Young (Author) , Pham, Minh Tu (Author) , Twu, Woan-Ing (Author) , Neufeldt, Christopher (Author) , Cortese, Mirko (Author) , Cerikan, Berati (Author) , Stahl, Yannick (Author) , Joecks, Sebastian (Author) , Tran, Cong Si (Author) , Lüchtenborg, Christian (Author) , V’kovski, Philip (Author) , Hörmann, Katrin (Author) , Müller, André C. (Author) , Zitzmann, Carolin (Author) , Haselmann, Uta (Author) , Beneke, Jürgen (Author) , Kaderali, Lars (Author) , Erfle, Holger (Author) , Thiel, Volker (Author) , Lohmann, Volker (Author) , Superti-Furga, Giulio (Author) , Brügger, Britta (Author) , Bartenschlager, Ralf (Author)
Format: Article (Journal)
Language:English
Published: 14 December 2021
In: Nature Communications
Year: 2021, Volume: 12, Pages: 1-15
ISSN:2041-1723
DOI:10.1038/s41467-021-27511-1
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-021-27511-1
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-021-27511-1
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Author Notes: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, Ralf Bartenschlager
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Summary: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.
Item Description:Gesehen am 02.03.2022
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-021-27511-1

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