Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2
Open Access
- 4 September 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science
- Vol. 369 (6508), 1249-+
- https://doi.org/10.1126/science.abc8665
Abstract
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.Funding Information
- Boehringer Ingelheim Fonds (Ph.D. fellowship)
- Deutsche Forschungsgemeinschaft (SFB/TRR-174)
- Deutsche Forschungsgemeinschaft (BE1814/15-1)
- Deutsche Forschungsgemeinschaft (BE1814/1-1)
- Deutsche Forschungsgemeinschaft (CRC-1279)
- Deutsche Forschungsgemeinschaft (CRC-1279)
- Deutsche Forschungsgemeinschaft (SPP-1923)
- Bundesministerium für Bildung und Forschung (RestrictSARS-CoV2)
- University Ulm Medical Center (L.SBN.0150)
- Deutsche Forschungsgemeinschaft (SPP-1923)
- Deutsche Forschungsgemeinschaft (SP1600/4-1)
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