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Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein
Jack Chun-Chieh Hsu1, Maudry Laurent-Rolle1,2, Joanna B Pawlak1,2
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
Abstract:
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.
Insights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein NSP14 inhibits host protein synthesis, crucial for viral replication. This shutdown mechanism also suppresses the host
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the COVID-19 pandemic.
- Viruses often disrupt host protein synthesis for replication.
- Understanding viral mechanisms is key to combating pandemics.
Purpose of the Study:
- To investigate SARS-CoV-2's mechanism for inhibiting host protein synthesis.
- To identify the specific viral protein responsible for translation inhibition.
- To explore the role of this inhibition in viral pathogenesis and host immune response.
Main Methods:
- Investigated SARS-CoV-2's effect on host protein synthesis.
- Identified SARS-CoV-2 nonstructural protein 14 (NSP14) as the key inhibitor.
- Assessed the impact of mutations in NSP14's active sites (exoribonuclease and N7-methyltransferase) on translation inhibition.
- Examined the role of the NSP14-NSP10 complex.
- Analyzed the effect of NSP14-mediated translational shutdown on type I interferon signaling and interferon-stimulated genes (ISGs).
Main Results:
- SARS-CoV-2 effectively shuts down host protein synthesis.
- Viral protein NSP14 is identified as the primary mediator of this translation inhibition.
- NSP14's exoribonuclease (ExoN) and N7-methyltransferase (N7-MTase) activities are essential for its translation inhibition function.
- The NSP14-NSP10 complex formation enhances translation inhibition.
- NSP14-induced translational shutdown prevents the induction of interferon-stimulated genes (ISGs), thereby inhibiting the type I interferon (IFN-I) response.
Conclusions:
- SARS-CoV-2 utilizes NSP14 to inhibit host protein synthesis, a conserved mechanism in human coronaviruses.
- NSP14's enzymatic activities (ExoN and N7-MTase) are critical for its role in translation inhibition and virus replication.
- By suppressing host protein synthesis and innate immune responses, SARS-CoV-2 effectively promotes its own propagation and pathogenesis.
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