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Nonstructural protein 1 of SARS-CoV-2 is a potent pathogenicity factor redirecting host protein synthesis machinery toward viral RNA

Shuai Yuan, Lei Peng, Jonathan J. Park, Yingxia Hu, Swapnil C. Devarkar, Matthew B. Dong, Shenping Wu, View ORCID ProfileSidi Chen, Ivan Lomakin, Yong Xiong
doi: https://doi.org/10.1101/2020.08.09.243451
Shuai Yuan
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
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Lei Peng
2Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
4Systems Biology Institute, Yale University, West Haven, CT, USA
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Jonathan J. Park
2Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
4Systems Biology Institute, Yale University, West Haven, CT, USA
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Yingxia Hu
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
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Swapnil C. Devarkar
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
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Matthew B. Dong
2Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
4Systems Biology Institute, Yale University, West Haven, CT, USA
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Shenping Wu
5Department of Pharmacology, Yale University, West Haven, CT, USA
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Sidi Chen
2Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
4Systems Biology Institute, Yale University, West Haven, CT, USA
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  • ORCID record for Sidi Chen
  • For correspondence: sidi.chen@yale.edu ivan.lomakin@yale.edu yong.xiong@yale.edu
Ivan Lomakin
3Department of Dermatology, Yale university school of medicine, New Haven, CT, USA
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  • For correspondence: sidi.chen@yale.edu ivan.lomakin@yale.edu yong.xiong@yale.edu
Yong Xiong
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
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  • For correspondence: sidi.chen@yale.edu ivan.lomakin@yale.edu yong.xiong@yale.edu
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Summary

The COVID-19 pandemic affects millions of people worldwide with a rising death toll. The causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), uses its nonstructural protein 1 (Nsp1) to redirect host translation machinery to the viral RNA by binding to the ribosome and suppressing cellular, but not viral, protein synthesis through yet unknown mechanisms. We show here that among all viral proteins, Nsp1 has the largest impact on host viability in the cells of human lung origin. Differential expression analysis of mRNA-seq data revealed that Nsp1 broadly alters the transcriptome in human cells. The changes include repression of major gene clusters in ribosomal RNA processing, translation, mitochondria function, cell cycle and antigen presentation; and induction of factors in transcriptional regulation. We further gained a mechanistic understanding of the Nsp1 function by determining the cryo-EM structure of the Nsp1-40S ribosomal subunit complex, which shows that Nsp1 inhibits translation by plugging the mRNA entry channel of the 40S. We also determined the cryo-EM structure of the 48S preinitiation complex (PIC) formed by Nsp1, 40S, and the cricket paralysis virus (CrPV) internal ribosome entry site (IRES) RNA, which shows that this 48S PIC is nonfunctional due to the incorrect position of the 3’ region of the mRNA. Results presented here elucidate the mechanism of host translation inhibition by SARS-CoV-2, provide insight into viral protein synthesis, and furnish a comprehensive understanding of the impacts from one of the most potent pathogenicity factors of SARS-CoV-2.

Highlights ORF screen identified Nsp1 as a major cellular pathogenicity factor of SARS-CoV-2

Nsp1 broadly alters the gene expression programs in human cells

Nsp1 inhibits translation by blocking mRNA entry channel

Nsp1 prevents physiological conformation of the 48S PIC

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

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Posted August 10, 2020.
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Nonstructural protein 1 of SARS-CoV-2 is a potent pathogenicity factor redirecting host protein synthesis machinery toward viral RNA
Shuai Yuan, Lei Peng, Jonathan J. Park, Yingxia Hu, Swapnil C. Devarkar, Matthew B. Dong, Shenping Wu, Sidi Chen, Ivan Lomakin, Yong Xiong
bioRxiv 2020.08.09.243451; doi: https://doi.org/10.1101/2020.08.09.243451
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Nonstructural protein 1 of SARS-CoV-2 is a potent pathogenicity factor redirecting host protein synthesis machinery toward viral RNA
Shuai Yuan, Lei Peng, Jonathan J. Park, Yingxia Hu, Swapnil C. Devarkar, Matthew B. Dong, Shenping Wu, Sidi Chen, Ivan Lomakin, Yong Xiong
bioRxiv 2020.08.09.243451; doi: https://doi.org/10.1101/2020.08.09.243451

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