Journal Article

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

Prasad, Vibhu, Lüchtenborg, Christian, Brügger, Britta, Stahl, Yannick, Twu, Woan-Ing, Beneke, Jürgen, Paul, David, Müller, André C., Hörmann, Katrin, Bartenschlager, Ralf, Erfle, Holger, V’kovski, Philip, Cortese, Mirko, Haselmann, Uta, Lohmann, Volker, Lee, Ji-Young, Kaderali, Lars, Superti-Furga, Giulio, Thiel, Volker, Cerikan, Berati, Neufeldt, Christopher J., Joecks, Sebastian, Tran, Cong Si, Tabata, Keisuke, Zitzmann, Carolin, Pham, Minh-Tu

2021

Overview

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. Double membrane vesicles (DMV) are used as replication organelles by several RNA viruses. Applying proteomics and lipidomics, Tabata and Prasad et al. find that two cellular acyltransferases (AGPAT1/2), responsible for synthesis of phosphatidic acid, play a role in the DMV-biogenesis of HCV and SARS-CoV-2, highlighting a common biogenesis mechanism for evolutionary distant positive-strand RNA viruses.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 1-Acylglycerol-3-Phosphate O-Acyltransferase / 14/19 / 14/28 / 147/143 / 38/47 / 60 APPLIED LIFE SCIENCES / 631/326/596/1905 / 631/326/596/4130 / 82/29 / 82/58 / 96/35 / Acyltransferase / Acyltransferases / Autophagosomes - metabolism / Autophagy / Biosynthesis / Cell Line / Cell Survival / COVID-19 / COVID-19 - virology / Dengue Virus / HEK293 Cells / Hepacivirus - genetics / Hepatitis / Hepatitis C / Hepatitis C virus / Humanities and Social Sciences / Humans / Lipids / Liver diseases / Membrane Proteins / Membrane vesicles / Membranes / multidisciplinary / Organelles / Phagocytosis / Phosphatidic acid / Phosphatidic Acids - metabolism / Phylogeny / Proteomics / Replication / RNA viruses / SARS-CoV-2 / SARS-CoV-2 - genetics / Science / Science (multidisciplinary) / Severe acute respiratory syndrome coronavirus 2 / Spike Glycoprotein, Coronavirus / Synthesis / Vesicles / Viral diseases / Viral Nonstructural Proteins / Viral Proteins / Virus Replication - physiology / Viruses / Zika Virus