Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 24, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2101161118
Keywords
NSP14; translation inhibition; coronavirus; immune evasion; innate immunity
Categories
Funding
- NIH [RO1 AI059167]
- Cancer Research Institute Irvington Postdoctoral Fellowship
- NIH/National Heart, Lung, and Blood Institute Grant [5 T32 HL 00797418]
- Rubicon research project by the Dutch Research Council [680-50-1531]
- [5 T32 HL 7974-19]
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SARS-CoV-2 shuts down host innate immune responses through the translation inhibition activity of NSP14, revealing insights into the pathogenesis of the virus.
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.
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