Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation
© 2021. The Author(s)..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Nature communications - 12(2021), 1 vom: 14. Dez., Seite 7276 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tabata, Keisuke [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.01.2022 Date Revised 04.04.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41467-021-27511-1 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Tabata, Keisuke |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation |
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| 500 | |a Date Revised 04.04.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Membrane Proteins |2 NLM | |
| 650 | 7 | |a NS4B protein, Dengue virus |2 NLM | |
| 650 | 7 | |a Phosphatidic Acids |2 NLM | |
| 650 | 7 | |a Spike Glycoprotein, Coronavirus |2 NLM | |
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| 700 | 1 | |a Prasad, Vibhu |e verfasserin |4 aut | |
| 700 | 1 | |a Paul, David |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Ji-Young |e verfasserin |4 aut | |
| 700 | 1 | |a Pham, Minh-Tu |e verfasserin |4 aut | |
| 700 | 1 | |a Twu, Woan-Ing |e verfasserin |4 aut | |
| 700 | 1 | |a Neufeldt, Christopher J |e verfasserin |4 aut | |
| 700 | 1 | |a Cortese, Mirko |e verfasserin |4 aut | |
| 700 | 1 | |a Cerikan, Berati |e verfasserin |4 aut | |
| 700 | 1 | |a Stahl, Yannick |e verfasserin |4 aut | |
| 700 | 1 | |a Joecks, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Tran, Cong Si |e verfasserin |4 aut | |
| 700 | 1 | |a Lüchtenborg, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a V'kovski, Philip |e verfasserin |4 aut | |
| 700 | 1 | |a Hörmann, Katrin |e verfasserin |4 aut | |
| 700 | 1 | |a Müller, André C |e verfasserin |4 aut | |
| 700 | 1 | |a Zitzmann, Carolin |e verfasserin |4 aut | |
| 700 | 1 | |a Haselmann, Uta |e verfasserin |4 aut | |
| 700 | 1 | |a Beneke, Jürgen |e verfasserin |4 aut | |
| 700 | 1 | |a Kaderali, Lars |e verfasserin |4 aut | |
| 700 | 1 | |a Erfle, Holger |e verfasserin |4 aut | |
| 700 | 1 | |a Thiel, Volker |e verfasserin |4 aut | |
| 700 | 1 | |a Lohmann, Volker |e verfasserin |4 aut | |
| 700 | 1 | |a Superti-Furga, Giulio |e verfasserin |4 aut | |
| 700 | 1 | |a Brügger, Britta |e verfasserin |4 aut | |
| 700 | 1 | |a Bartenschlager, Ralf |e verfasserin |4 aut | |
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