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A unifying structural and functional model of the coronavirus replication organelle: tracking down RNA synthesis

View ORCID ProfileEric J. Snijder, View ORCID ProfileRonald W.A.L. Limpens, Adriaan H. de Wilde, View ORCID ProfileAnja W. M. de Jong, Jessika C. Zevenhoven-Dobbe, Helena J. Maier, View ORCID ProfileFrank F.G.A. Faas, View ORCID ProfileAbraham J. Koster, View ORCID ProfileMontserrat Bárcena
doi: https://doi.org/10.1101/2020.03.24.005298
Eric J. Snijder
1Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
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  • For correspondence: m.barcena@lumc.nl e.j.snijder@lumc.nl
Ronald W.A.L. Limpens
2Section Electron Microscopy, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
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Adriaan H. de Wilde
1Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
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Anja W. M. de Jong
2Section Electron Microscopy, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
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Jessika C. Zevenhoven-Dobbe
1Molecular Virology Laboratory, Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
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Helena J. Maier
3The Pirbright Institute, Pirbright, Surrey, United Kingdom
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Frank F.G.A. Faas
2Section Electron Microscopy, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
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Abraham J. Koster
2Section Electron Microscopy, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
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Montserrat Bárcena
2Section Electron Microscopy, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, The Netherlands
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  • For correspondence: m.barcena@lumc.nl e.j.snijder@lumc.nl
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Abstract

Zoonotic coronavirus (CoV) infections, like those responsible for the current SARS-CoV-2 epidemic, cause grave international public health concern. In infected cells, the CoV RNA-synthesizing machinery associates with modified endoplasmic reticulum membranes that are transformed into the viral replication organelle (RO). While double-membrane vesicles (DMVs) appear to be a pan-coronavirus RO element, studies to date describe an assortment of additional coronavirus-induced membrane structures. Despite much speculation, it remains unclear which RO element(s) accommodate viral RNA synthesis. Here we provide detailed 2D and 3D analyses of CoV ROs and show that diverse CoVs essentially induce the same membrane modifications, including the small open double-membrane spherules (DMSs) previously thought to be restricted to gamma- and delta-CoV infections and proposed as sites of replication. Metabolic labelling of newly-synthesized viral RNA followed by quantitative EM autoradiography revealed abundant viral RNA synthesis associated with DMVs in cells infected with the beta-CoVs MERS-CoV and SARS-CoV, and the gamma-CoV infectious bronchitis virus. RNA synthesis could not be linked to DMSs or any other cellular or virus-induced structure. Our results provide a unifying model of the CoV RO and clearly establish DMVs as the central hub for viral RNA synthesis and a potential drug target in coronavirus infection.

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Posted March 24, 2020.
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A unifying structural and functional model of the coronavirus replication organelle: tracking down RNA synthesis
Eric J. Snijder, Ronald W.A.L. Limpens, Adriaan H. de Wilde, Anja W. M. de Jong, Jessika C. Zevenhoven-Dobbe, Helena J. Maier, Frank F.G.A. Faas, Abraham J. Koster, Montserrat Bárcena
bioRxiv 2020.03.24.005298; doi: https://doi.org/10.1101/2020.03.24.005298
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A unifying structural and functional model of the coronavirus replication organelle: tracking down RNA synthesis
Eric J. Snijder, Ronald W.A.L. Limpens, Adriaan H. de Wilde, Anja W. M. de Jong, Jessika C. Zevenhoven-Dobbe, Helena J. Maier, Frank F.G.A. Faas, Abraham J. Koster, Montserrat Bárcena
bioRxiv 2020.03.24.005298; doi: https://doi.org/10.1101/2020.03.24.005298

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