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

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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. Here, we show that Nsp1 from SARS-CoV-2 binds to the 40S ribosomal subunit, resulting in shutdown of mRNA translation both in vitro and in cells. Structural analysis by cryo-electron microscopy (cryo-EM) 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 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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Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the fundamental physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. Here, we provide an overview of the pathophysiology of SARS-CoV-2 infection. We describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression. From nascent reports describing SARS-CoV-2, we make inferences on the basis of the parallel pathophysiological and immunological features of the other human coronaviruses targeting the lower respiratory tract — severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Finally, we highlight the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation.

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Author and article information

Journal

Journal ID (nlm-ta): Science

Journal ID (iso-abbrev): Science

Journal ID (publisher-id): SCIENCE

Title: Science (New York, N.y.)

Publisher: American Association for the Advancement of Science

ISSN (Print): 0036-8075

ISSN (Electronic): 1095-9203

Publication date (Electronic): 17 July 2020

Electronic Location Identifier: eabc8665

Affiliations

[1 ]Gene Center Munich, Department of Biochemistry, University of Munich, Munich, Germany.

[2 ]Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany.

[3 ]Laboratory of Functional Genome Analysis, University of Munich, Munich, Germany.

Author notes

[*]

These authors contributed equally to this work.

[† ]Corresponding author. Email: beckmann@ 123456genzentrum.lmu.de (R.B.); konstantin.sparrer@ 123456uni-ulm.de (K.M.J.S.)

Author information

Matthias Thoms https://orcid.org/0000-0001-8084-6097

Robert Buschauer https://orcid.org/0000-0002-5794-4841

Michael Ameismeier https://orcid.org/0000-0002-1194-3448

Lennart Koepke https://orcid.org/0000-0001-9788-1972

Timo Denk https://orcid.org/0000-0002-0761-3294

Maximilian Hirschenberger https://orcid.org/0000-0001-8766-1271

Hanna Kratzat https://orcid.org/0000-0001-5849-6131

Timur Mackens-Kiani https://orcid.org/0000-0003-0385-5875

Jingdong Cheng https://orcid.org/0000-0003-4442-377X

Thomas Fröhlich https://orcid.org/0000-0002-4709-3211

Otto Berninghausen https://orcid.org/0000-0002-9255-0522

Thomas Becker https://orcid.org/0000-0001-8458-2738

Frank Kirchhoff https://orcid.org/0000-0002-7052-2360

Konstantin M. J. Sparrer https://orcid.org/0000-0002-8682-1779

Roland Beckmann https://orcid.org/0000-0003-4291-3898

Article

Publisher ID: abc8665

DOI: 10.1126/science.abc8665

PMC ID: 7402621

PubMed ID: 32680882

SO-VID: 823abba8-e11e-4010-aa64-18765f583135

Copyright © Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 18 May 2020

Date accepted : 13 July 2020