Key result
SARS-CoV-2 Nsp1 blocks the ribosome mRNA entry tunnel to shut down translation and innate immunity.
Why the study?
SARS-CoV-2 nonstructural protein 1 suppresses host gene expression by ribosome association via an unknown mechanism.
Structural characterization of SARS-CoV-2 Nsp1 binding to the ribosome mRNA entry tunnel provides a mechanistic basis for viral immune evasion and a potential target for structure-based drug design.
May enable structure-guided antivirals against immune evasion; leaves open human translation from animal data.
SARS-CoV-2 is the causative agent of the current COVID-19 pandemic. A major virulence factor of SARS-CoVs is the nonstructural protein 1 (Nsp1) which suppresses host gene expression by ribosome association via an unknown mechanism. Here, we show that Nsp1 from SARS-CoV-2 binds to 40S and 80S ribosomes, resulting in shutdown of capped mRNA translation both in vitro and in cells. Structural analysis by cryo-electron microscopy (cryo-EM) of in vitro reconstituted Nsp1-40S and of native human Nsp1-ribosome complexes revealed that the Nsp1 C-terminus binds to and obstructs the mRNA entry tunnel. Thereby, Nsp1 effectively blocks RIG-I-dependent innate immune responses that would otherwise facilitate clearance of the infection. Thus, the structural characterization of the inhibitory mechanism of Nsp1 may aid structure-based drug design against SARS-CoV-2.
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Thoms et al. (2020) studied SARS-CoV-2 infection (in vitro model). SARS-CoV-2 Nsp1 protein vs. Nsp1 mutants (K164A/H165A), Nsp7, or empty vector was evaluated on Ribosome binding and translation inhibition. SARS-CoV-2 Nsp1 binds to the 40S and 80S ribosomes, obstructing the mRNA entry tunnel and effectively shutting down capped mRNA translation and RIG-I-dependent innate immune responses.
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