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

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

doi:10.1038/s41467-021-27511-1

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.

Highlights

1234567890():,; Double membrane vesicles (DMVs) serve as replication organelles of plus-strand RNA viruses such as hepatitis C virus (HCV) and SARS-CoV-2
Identification of acylglycerolphosphate acyltransferase (AGPAT) as critical host cell factors contributing to HCV replication
Given that AGPAT1 and 2 are important for double-membrane vesicles (DMVs) formation and their enzymatic activity is required for HCV replication, we focused on their reaction product, i.e. the lipid phosphatidic acid (PA)

Summary

Introduction

1234567890():,; Double membrane vesicles (DMVs) serve as replication organelles of plus-strand RNA viruses such as hepatitis C virus (HCV) and SARS-CoV-2. This biological distinction is reflected by their phylogenetic distance with HCV belonging to the Flaviviridae and SARS-CoV-2 being a member of the Coronaviridae virus family[3] In spite of these differences, both viruses possess a single strand RNA genome of positive polarity that is replicated in membranous vesicles in the cytoplasm of infected cells[4,5]. These vesicles are induced by viral proteins, in concert with cellular factors, and composed of two membrane bilayers, corresponding to double-membrane vesicles (DMVs). We show that common host cell factors are exploited by the phylogenetically distant HCV and SARSCoV-2 to build up their cytoplasmic replication organelle

Methods

Results

Conclusion