Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein

The ongoing COVID-19 pandemic has caused an unprecedented global health crisis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19. Subversion of host protein synthesis is a common strategy that pathogenic viruses use to replicate and propagate in their h...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-06, Vol.118 (24), p.1-9
Main Authors: Hsu, Jack Chun-Chieh, Laurent-Rolle, Maudry, Pawlak, Joanna B., Wilen, Craig B., Cresswell, Peter
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Chlorocebus aethiops
Coronaviruses
COVID-19
COVID-19 - immunology
Exoribonucleases - immunology
Global health
Humans
Immune Evasion
Immune response
Immune system
Immunity, Innate
Innate immunity
Interferon
Methyltransferase
Mutation
Pandemics
Pathogenesis
Protein biosynthesis
Protein Biosynthesis - immunology
Protein synthesis
Proteins
Public health
SARS-CoV-2 - immunology
Severe acute respiratory syndrome coronavirus 2
Shutdowns
Translation
Vero Cells
Viral diseases
Viral Nonstructural Proteins - immunology
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Summary:The ongoing COVID-19 pandemic has caused an unprecedented global health crisis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19. Subversion of host protein synthesis is a common strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to shut down host protein synthesis and that SARS-CoV-2 nonstructural protein NSP14 exerts this activity. We show that the translation inhibition activity of NSP14 is conserved in human coronaviruses. NSP14 is required for virus replication through contribution of its exoribonuclease (ExoN) and N7-methyltransferase (N7-MTase) activities. Mutations in the ExoN or N7-MTase active sites of SARS-CoV-2 NSP14 abolish its translation inhibition activity. In addition, we show that the formation of NSP14−NSP10 complex enhances translation inhibition executed by NSP14. Consequently, the translational shutdown by NSP14 abolishes the type I interferon (IFN-I)-dependent induction of interferon-stimulated genes (ISGs). Together, we find that SARS-CoV-2 shuts down host innate immune responses via a translation inhibitor, providing insights into the pathogenesis of SARS-CoV-2.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.2101161118