SARS-CoV-2 Nsp1 binds ribosomal mRNA channel to inhibit translation
cell biology immunology/immunity structural biology virology
Authors:Schubert, K; Karousis, E. D. et al.
Link to paper: https://www.biorxiv.org/content/10.1101/2020.07.07.191676v1
Tags: Cell Biology, Virology, Structural Biology, Modelling, Immunology/Immunity
Nsp1 inhibits translation in SARS-COV-2 infected cells by interacting with ribosomes.
The C-terminal region of the SARS-CoV-2 Nsp1 binds to the ribosomal mRNA entry site, which inhibits classical mRNA translation by steric hindrance.
Nsp1 mutants (C-terminal) are unable to bind to ribosomes, which leads to unaffected translation.
The non-structural protein 1 (Nsp1) of SARS-CoV-2 is able to induce global inhibition of translation in infected cells. Authors show that this happens by binding of Nsp1 to the 40S subunit in ribosomal complexes. Cryo-EM analysis of Nsp1-40S complexes allowed the construction of an atomic model and the determination of Nsp1’s localization. More specifically, the C-terminal region of Nsp1 docks in the mRNA entrance channel of the ribosome, which inhibits classical mRNA translation. Based on the structural model obtained by cryo-EM, authors produced several mutants of Nsp1, focusing on C-terminal modifications. As opposed to wild type Nsp1, its mutants were unable to inhibit translation in human cells. An in vitro translation system with Renilla Luciferase reporters showed that mRNAs containing the full-length 5΄UTR of the SARS-CoV-2 genomic RNA had significantly higher translation rates in comparison to the ones containing native 5’UTR. This suggests viral mRNA is preferentially translated, which would explain maintenance of viral replication in a scenario where most of the ribosomes are being inhibited by Nsp1.
Impact for SARS-CoV2/COVID19 research efforts
The characterization of Nsp1-ribosome interactions, which are critical for controlling cellular response to SARS-CoV-2 infection, might be relevant to design attenuated strains of the virus for vaccine development.
In silico study
In vitro study
Strengths and limitations of the paper
Novelty: Shows for the first time that the mRNAs containing 5’UTR from SARS-CoV-2 also have their translation inhibited by Nsp1, but are preferentially translated, which might explain how viral replication is kept in a scenario of global translation inhibition, where few ribosomes are available.
Standing in the field: Concerning Nsp1-ribosomal structures, it confirms findings from https://www.biorxiv.org/content/10.1101/2020.05.18.102467v1
Appropriate statistics: yes
Viral model used: none
Translatability: Nsp1 mutations as a target for design of attenuated virus (vaccination setups)
Experiments are limited to cell lines
Doesn’t address whether different cellular mRNAs are more or less impacted by Nsp1 inhibition