Cell Reports
Volume 37, Issue 3, 19 October 2021, 109841
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Article
The N-terminal domain of SARS-CoV-2 nsp1 plays key roles in suppression of cellular gene expression and preservation of viral gene expression

https://doi.org/10.1016/j.celrep.2021.109841Get rights and content
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Highlights

  • SARS-CoV-2 Nsp1 inhibits host mRNA translation and promotes mRNA decay

  • The N-terminal and central domains of Nsp1 are required for host shutoff

  • Nsp1 N terminus stabilizes Nsp1 binding to the 40S ribosomal subunit

  • Mutation of Nsp1 N-terminal residues abrogates escape of SARS-CoV-2 leader mRNA

Summary

Nonstructural protein 1 (nsp1) is a coronavirus (CoV) virulence factor that restricts cellular gene expression by inhibiting translation through blocking the mRNA entry channel of the 40S ribosomal subunit and by promoting mRNA degradation. We perform a detailed structure-guided mutational analysis of severe acute respiratory syndrome (SARS)-CoV-2 nsp1, revealing insights into how it coordinates these activities against host but not viral mRNA. We find that residues in the N-terminal and central regions of nsp1 not involved in docking into the 40S mRNA entry channel nonetheless stabilize its association with the ribosome and mRNA, both enhancing its restriction of host gene expression and enabling mRNA containing the SARS-CoV-2 leader sequence to escape translational repression. These data support a model in which viral mRNA binding functionally alters the association of nsp1 with the ribosome, which has implications for drug targeting and understanding how engineered or emerging mutations in SARS-CoV-2 nsp1 could attenuate the virus.

Keywords

SARS-CoV-2
SARS
coronavirus
nsp1
translation
RNA
ribosome
nuclease

Data and code availability

  • All data reported in this paper will be shared by the lead contact upon request.

  • This paper does not report original code.

  • Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Cited by (0)

9

These authors contributed equally

10

Lead contact