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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Bibliographic Details
Published in:	Nature communications 2021-12, Vol.12 (1), p.7276-15, Article 7276
Main Authors:	Tabata, Keisuke, Prasad, Vibhu, Paul, David, Lee, Ji-Young, Pham, Minh-Tu, Twu, Woan-Ing, Neufeldt, Christopher J, Cortese, Mirko, Cerikan, Berati, Stahl, Yannick, Joecks, Sebastian, Tran, Cong Si, Lüchtenborg, Christian, V'kovski, Philip, Hörmann, Katrin, Müller, André C, Zitzmann, Carolin, Haselmann, Uta, Beneke, Jürgen, Kaderali, Lars, Erfle, Holger, Thiel, Volker, Lohmann, Volker, Superti-Furga, Giulio, Brügger, Britta, Bartenschlager, Ralf
Format:	Article
Language:	eng
Subjects:	1-Acylglycerol-3-Phosphate O-Acyltransferase Acyltransferase Acyltransferases Autophagosomes - metabolism Autophagy Biosynthesis Cell Line Cell Survival COVID-19 COVID-19 - virology Dengue Virus HEK293 Cells Hepacivirus - genetics Hepatitis Hepatitis C Humans Lipids Liver diseases Membrane Proteins Membrane vesicles Membranes Organelles Phagocytosis Phosphatidic acid Phosphatidic Acids - metabolism Phylogeny Proteomics Replication RNA viruses SARS-CoV-2 - genetics Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Spike Glycoprotein, Coronavirus Synthesis Vesicles Viral diseases Viral Nonstructural Proteins Viral Proteins Virus Replication - physiology Viruses Zika Virus
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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.
ISSN:	2041-1723 2041-1723