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

Kumar, Pravin ; Schexnaydre, Erin ; Rafie, Karim ; Kurata, Tatsuaki LU ; Terenin, Ilya ; Hauryliuk, Vasili LU orcid and Carlson, Lars-Anders (2022) In FEBS Letters 596(9). p.1203-1213
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... (More)

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.

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author
; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Nsp1, SARS-CoV-2, COVID-19, pathogenicity, ribosome, translation, virus
in
FEBS Letters
volume
596
issue
9
pages
1203 - 1213
publisher
Wiley-Blackwell
external identifiers
  • scopus:85129091882
  • pmid:35434785
ISSN
1873-3468
DOI
10.1002/1873-3468.14354
language
English
LU publication?
yes
additional info
This article is protected by copyright. All rights reserved.
id
6077de65-fb43-4101-8278-cc74aba4f0d3
date added to LUP
2022-04-19 11:10:16
date last changed
2024-06-27 13:14:36
@article{6077de65-fb43-4101-8278-cc74aba4f0d3,
  abstract     = {{<p>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.</p>}},
  author       = {{Kumar, Pravin and Schexnaydre, Erin and Rafie, Karim and Kurata, Tatsuaki and Terenin, Ilya and Hauryliuk, Vasili and Carlson, Lars-Anders}},
  issn         = {{1873-3468}},
  keywords     = {{Nsp1; SARS-CoV-2; COVID-19; pathogenicity; ribosome; translation; virus}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{9}},
  pages        = {{1203--1213}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{FEBS Letters}},
  title        = {{Clinically observed deletions in SARS-CoV-2 Nsp1 affect its stability and ability to inhibit translation}},
  url          = {{http://dx.doi.org/10.1002/1873-3468.14354}},
  doi          = {{10.1002/1873-3468.14354}},
  volume       = {{596}},
  year         = {{2022}},
}