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

By M. Thoms, R. Buschauer, M. Ameismeier, L. Koepke, T. Denk, M. Hirschenberger, H. Kratzat, Manuel Hayn, T. Mackens-Kiani, Jingdong Cheng and 8 more. Science, 2020

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A viral block on host protein synthesis As the coronavirus disease 2019 (COVID-19) pandemic continues to cause devastation, scientists race to increase their understanding of the disease-causing severe acute respiratory syndrome coronavirus 2. Once inside host cells, not only does the virus hijack the cells' translational machinery to make viral proteins, but the virulence factor nonstructural protein 1 (Nsp1) also shuts down translation of host messenger RNA. Thoms et al. determined a 2.6-angstrom resolution cryo–electron microscopy structure of a reconstituted complex of Nsp1 bound to the human 40S ribosomal subunit and showed that Nsp1 blocks the messenger RNA entry tunnel. A structural inventory of native Nsp1-ribosome complexes from human cells confirms this mechanism. Cellular studies show that the translational shutdown almost completely inhibits the innate immune response. The binding pocket on the ribosome may be a target for drugs to treat COVID-19. Science, this issue p. 1249 SARS-CoV-2 protein Nsp1 suppresses host translation and immune responses by blocking the ribosomal mRNA entry tunnel. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the current coronavirus disease 2019 (COVID-19) pandemic. A major virulence factor of SARS-CoVs is the nonstructural protein 1 (Nsp1), which suppresses host gene expression by ribosome association. Here, we show that Nsp1 from SARS-CoV-2 binds to the 40S ribosomal subunit, resulting in shutdown of messenger RNA (mRNA) translation both in vitro and in cells. Structural analysis by cryo–electron microscopy of in vitro–reconstituted Nsp1-40S and various native Nsp1-40S and -80S complexes revealed that the Nsp1 C terminus binds to and obstructs the mRNA entry tunnel. Thereby, Nsp1 effectively blocks retinoic acid–inducible gene 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.

Subfields: Immunology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/251a3e6d9753363bf8de25d4f5cbd78644fdab41