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Clinically observed deletions in SARS-CoV-2 Nsp1 affect its stability and ability to inhibit translation.

ABSTRACT: Nonstructural protein 1 (Nsp1) of SARS-CoV-2 inhibits host cell translation through an interaction between its C-terminal domain and the 40S ribosome. The N-terminal domain (NTD) of Nsp1 is a target of recurring deletions, some of which are associated with altered COVID-19 disease progression. Here, we characterize the efficiency of translational inhibition by clinically observed Nsp1 deletion variants. We show that a frequent deletion of residues 79-89 severely reduces the ability of Nsp1 to inhibit translation while not abrogating Nsp1 binding to the 40S. Notably, while the SARS-CoV-2 5' untranslated region enhances translation of mRNA, it does not protect from Nsp1-mediated inhibition. Finally, thermal stability measurements and structure predictions reveal a correlation between stability of the NTD and the efficiency of translation inhibition.

SUBMITTER: Kumar P

PROVIDER: S-EPMC9081967 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Clinically observed deletions in SARS-CoV-2 Nsp1 affect its stability and ability to inhibit translation.

Kumar Pravin P Schexnaydre Erin E Rafie Karim K Kurata Tatsuaki T Terenin Ilya I Hauryliuk Vasili V Carlson Lars-Anders LA

FEBS letters 20220425 9

Nonstructural protein 1 (Nsp1) of SARS-CoV-2 inhibits host cell translation through an interaction between its C-terminal domain and the 40S ribosome. The N-terminal domain (NTD) of Nsp1 is a target of recurring deletions, some of which are associated with altered COVID-19 disease progression. Here, we characterize the efficiency of translational inhibition by clinically observed Nsp1 deletion variants. We show that a frequent deletion of residues 79-89 severely reduces the ability of Nsp1 to in ...[more]

PMID: 35434785

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