Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2

Matthias Thoms; Robert Buschauer; Michael Ameismeier; Lennart Koepke; Timo Denk; Maximilian Hirschenberger; Hanna Kratzat; Manuel Hayn; Timur Mackens‐Kiani; Jingdong Cheng; Jan Hendrik Straub; Christina Martina Stürzel; Thomas Fröhlich; Otto Berninghausen; Thomas A. Becker; Frank Kirchhoff; Konstantin M. J. Sparrer; Roland Beckmann

doi:10.1126/science.abc8665

Molecular BiologyScienceJul 17, 2020

Peer-reviewed journal article

Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2

Matthias Thoms iD, Robert Buschauer iD, Michael Ameismeier iD, Lennart Koepke iD, Timo Denk iD, Maximilian Hirschenberger iD, Hanna Kratzat iD, Manuel Hayn iD, Timur Mackens‐Kiani iD, Jingdong Cheng iD, Jan Hendrik Straub, Christina Martina Stürzel, Thomas Fröhlich iD, Otto Berninghausen iD, Thomas A. Becker iD, Frank Kirchhoff iD, Konstantin M. J. Sparrer iD, Roland Beckmann iD

Abstract

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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