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

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; ... (2021). Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation. Nature Communications, 12(1), p. 7276. Springer Nature 10.1038/s41467-021-27511-1

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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 Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute for Infectious Diseases > Research
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Virology and Immunology
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP)

UniBE Contributor:

V'kovski, Philip and Thiel, Volker Earl

Subjects:

500 Science
500 Science > 570 Life sciences; biology
500 Science > 590 Animals (Zoology)
600 Technology > 610 Medicine & health
600 Technology > 630 Agriculture

ISSN:

2041-1723

Publisher:

Springer Nature

Language:

English

Submitter:

Katharina Gerber-Paizs

Date Deposited:

24 Feb 2022 08:29

Last Modified:

05 Dec 2022 16:08

Publisher DOI:

10.1038/s41467-021-27511-1

PubMed ID:

34907161

BORIS DOI:

10.48350/165639

URI:

https://boris.unibe.ch/id/eprint/165639

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