SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis

Yaara Finkel; Avi Gluck; Aharon Nachshon; Roni Winkler; Tal Fisher; Batsheva Rozman; Orel Mizrahi; Yoav Lubelsky; Binyamin Zuckerman; Boris Slobodin; Yfat Yahalom-Ronen; Hadas Tamir; Igor Ulitsky; Tomer Israely; Nir Paran; Michal Schwartz; Noam Stern-Ginossar

doi:10.1038/s41586-021-03610-3

SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis

Yaara Finkel, Avi Gluck, Aharon Nachshon, Roni Winkler, Tal Fisher, Batsheva Rozman, Orel Mizrahi, Yoav Lubelsky, Binyamin Zuckerman, Boris Slobodin, Yfat Yahalom-Ronen, Hadas Tamir, Igor Ulitsky, Tomer Israely, Nir Paran, Michal Schwartz, Noam Stern-Ginossar

Research output: Contribution to journal › Article › peer-review

154 Scopus citations

Abstract

The coronavirus SARS-CoV-2 is the cause of the ongoing pandemic of COVID-19¹. Coronaviruses have developed a variety of mechanisms to repress host mRNA translation to allow the translation of viral mRNA, and concomitantly block the cellular innate immune response^2,3. Although several different proteins of SARS-CoV-2 have previously been implicated in shutting off host expression^4–7, a comprehensive picture of the effects of SARS-CoV-2 infection on cellular gene expression is lacking. Here we combine RNA sequencing, ribosome profiling and metabolic labelling of newly synthesized RNA to comprehensively define the mechanisms that are used by SARS-CoV-2 to shut off cellular protein synthesis. We show that infection leads to a global reduction in translation, but that viral transcripts are not preferentially translated. Instead, we find that infection leads to the accelerated degradation of cytosolic cellular mRNAs, which facilitates viral takeover of the mRNA pool in infected cells. We reveal that the translation of transcripts that are induced in response to infection (including innate immune genes) is impaired. We demonstrate this impairment is probably mediated by inhibition of nuclear mRNA export, which prevents newly transcribed cellular mRNA from accessing ribosomes. Overall, our results uncover a multipronged strategy that is used by SARS-CoV-2 to take over the translation machinery and to suppress host defences.

Original language	English
Pages (from-to)	240-245
Number of pages	6
Journal	Nature
Volume	594
Issue number	7862
DOIs	https://doi.org/10.1038/s41586-021-03610-3
State	Published - 10 Jun 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.

Funding

Acknowledgements We thank members of the laboratory of N.S.-G. for providing valuable feedback; N. Krogan for the SARS-CoV-2 ORF expression plasmids; G. Jona and Weizmann Bacteriology and Genomic Repository Units for technical assistance; members of the virology research group at the IIBR for their contribution and support; and S. Weiss for biosafety guidance. This study was supported by a research grant from Weizmann Corona Response Fund. Work in the laboratory of N.S.-G. is supported by a European Research Council consolidator grant (CoG-2019-864012). N.S.-G. is an incumbent of the Skirball Career Development Chair in New Scientists and is a member of the European Molecular Biology Organization (EMBO) Young Investigator Program.

Funders	Funder number
Weizmann Corona Response Fund
European Commission	CoG-2019-864012

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Finkel, Y., Gluck, A., Nachshon, A., Winkler, R., Fisher, T., Rozman, B., Mizrahi, O., Lubelsky, Y., Zuckerman, B., Slobodin, B., Yahalom-Ronen, Y., Tamir, H., Ulitsky, I., Israely, T., Paran, N., Schwartz, M., & Stern-Ginossar, N. (2021). SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis. Nature, 594(7862), 240-245. https://doi.org/10.1038/s41586-021-03610-3

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abstract = "The coronavirus SARS-CoV-2 is the cause of the ongoing pandemic of COVID-191. Coronaviruses have developed a variety of mechanisms to repress host mRNA translation to allow the translation of viral mRNA, and concomitantly block the cellular innate immune response2,3. Although several different proteins of SARS-CoV-2 have previously been implicated in shutting off host expression4–7, a comprehensive picture of the effects of SARS-CoV-2 infection on cellular gene expression is lacking. Here we combine RNA sequencing, ribosome profiling and metabolic labelling of newly synthesized RNA to comprehensively define the mechanisms that are used by SARS-CoV-2 to shut off cellular protein synthesis. We show that infection leads to a global reduction in translation, but that viral transcripts are not preferentially translated. Instead, we find that infection leads to the accelerated degradation of cytosolic cellular mRNAs, which facilitates viral takeover of the mRNA pool in infected cells. We reveal that the translation of transcripts that are induced in response to infection (including innate immune genes) is impaired. We demonstrate this impairment is probably mediated by inhibition of nuclear mRNA export, which prevents newly transcribed cellular mRNA from accessing ribosomes. Overall, our results uncover a multipronged strategy that is used by SARS-CoV-2 to take over the translation machinery and to suppress host defences.",

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Finkel, Y, Gluck, A, Nachshon, A, Winkler, R, Fisher, T, Rozman, B, Mizrahi, O, Lubelsky, Y, Zuckerman, B, Slobodin, B, Yahalom-Ronen, Y, Tamir, H, Ulitsky, I, Israely, T, Paran, N, Schwartz, M & Stern-Ginossar, N 2021, 'SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis', Nature, vol. 594, no. 7862, pp. 240-245. https://doi.org/10.1038/s41586-021-03610-3

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AU - Finkel, Yaara

AU - Gluck, Avi

AU - Nachshon, Aharon

AU - Winkler, Roni

AU - Fisher, Tal

AU - Rozman, Batsheva

AU - Mizrahi, Orel

AU - Lubelsky, Yoav

AU - Zuckerman, Binyamin

AU - Slobodin, Boris

AU - Yahalom-Ronen, Yfat

AU - Tamir, Hadas

AU - Ulitsky, Igor

AU - Israely, Tomer

AU - Paran, Nir

AU - Schwartz, Michal

AU - Stern-Ginossar, Noam

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AB - The coronavirus SARS-CoV-2 is the cause of the ongoing pandemic of COVID-191. Coronaviruses have developed a variety of mechanisms to repress host mRNA translation to allow the translation of viral mRNA, and concomitantly block the cellular innate immune response2,3. Although several different proteins of SARS-CoV-2 have previously been implicated in shutting off host expression4–7, a comprehensive picture of the effects of SARS-CoV-2 infection on cellular gene expression is lacking. Here we combine RNA sequencing, ribosome profiling and metabolic labelling of newly synthesized RNA to comprehensively define the mechanisms that are used by SARS-CoV-2 to shut off cellular protein synthesis. We show that infection leads to a global reduction in translation, but that viral transcripts are not preferentially translated. Instead, we find that infection leads to the accelerated degradation of cytosolic cellular mRNAs, which facilitates viral takeover of the mRNA pool in infected cells. We reveal that the translation of transcripts that are induced in response to infection (including innate immune genes) is impaired. We demonstrate this impairment is probably mediated by inhibition of nuclear mRNA export, which prevents newly transcribed cellular mRNA from accessing ribosomes. Overall, our results uncover a multipronged strategy that is used by SARS-CoV-2 to take over the translation machinery and to suppress host defences.

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SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis

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