scholarly journals Nonstructural Protein 1 of SARS-CoV-2 Is a Potent Pathogenicity Factor Redirecting Host Protein Synthesis Machinery toward Viral RNA

2020 ◽  
Vol 80 (6) ◽  
pp. 1055-1066.e6 ◽  
Author(s):  
Shuai Yuan ◽  
Lei Peng ◽  
Jonathan J. Park ◽  
Yingxia Hu ◽  
Swapnil C. Devarkar ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Nonstructural Protein ◽  
Viral Rna ◽  
Host Protein ◽  
Pathogenicity Factor ◽  
Nonstructural Protein 1 ◽  
Protein Synthesis Machinery ◽  
Host Protein Synthesis

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

2020 ◽  
Author(s):  
Shuai Yuan ◽  
Lei Peng ◽  
Jonathan J. Park ◽  
Yingxia Hu ◽  
Swapnil C. Devarkar ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Viral Protein ◽  
Nonstructural Protein ◽  
Differential Expression Analysis ◽  
Human Cells ◽  
Viral Rna ◽  
Host Protein ◽  
Viral Protein Synthesis ◽  
Pathogenicity Factor ◽  
Nonstructural Protein 1

SummaryThe 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.HighlightsORF screen identified Nsp1 as a major cellular pathogenicity factor of SARS-CoV-2Nsp1 broadly alters the gene expression programs in human cellsNsp1 inhibits translation by blocking mRNA entry channelNsp1 prevents physiological conformation of the 48S PIC

scholarly journals Targeting Stem-loop 1 of the SARS-CoV-2 5’UTR to suppress viral translation and Nsp1 evasion

2021 ◽  
Author(s):  
Setu M. Vora ◽  
Pietro Fontana ◽  
Valerie Leger ◽  
Ying Zhang ◽  
Tian-Min Fu ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Nonstructural Protein ◽  
Host Protein ◽  
Locked Nucleic Acid ◽  
Viral Protein Synthesis ◽  
Stem Loop ◽  
Viral Translation ◽  
Nonstructural Protein 1 ◽  
Host Protein Synthesis

SARS-CoV-2 is a highly pathogenic virus that evades anti-viral immunity by interfering with host protein synthesis, mRNA stability, and protein trafficking. The SARS-CoV-2 nonstructural protein 1 (Nsp1) uses its C-terminal domain to block the mRNA entry channel of the 40S ribosome to inhibit host protein synthesis. However, how SARS-CoV-2 circumvents Nsp1-mediated suppression for viral protein synthesis and if the mechanism can be targeted therapeutically remain unclear. Here we show that N- and C-terminal domains of Nsp1 coordinate to drive a tuned ratio of viral to host translation, likely to maintain a certain level of host fitness while maximizing replication. We reveal that the SL1 region of the SARS-CoV-2 5’ UTR is necessary and sufficient to evade Nsp1-mediated translational suppression. Targeting SL1 with locked nucleic acid antisense oligonucleotides (ASOs) inhibits viral translation and makes SARS-CoV-2 5’ UTR vulnerable to Nsp1 suppression, hindering viral replication in vitro at a nanomolar concentration. Thus, SL1 allows Nsp1 to switch infected cells from host to SARS-CoV-2 translation, presenting a therapeutic target against COVID-19 that is conserved among immune-evasive variants. This unique strategy of unleashing a virus’ own virulence mechanism against itself could force a critical trade off between drug resistance and pathogenicity.

scholarly journals Translational shutdown and evasion of the innate immune response by SARS-CoV-2 NSP14 protein

2021 ◽  
Vol 118 (24) ◽  
pp. e2101161118
Author(s):  
Jack Chun-Chieh Hsu ◽  
Maudry Laurent-Rolle ◽  
Joanna B. Pawlak ◽  
Craig B. Wilen ◽  
Peter Cresswell
Keyword(s):  
Protein Synthesis ◽  
Active Sites ◽  
Nonstructural Protein ◽  
Innate Immune ◽  
Host Protein ◽  
Type I ◽  
Inhibition Activity ◽  
Health Crisis ◽  
Translation Inhibition ◽  
Host Protein Synthesis

The ongoing COVID-19 pandemic has caused an unprecedented global health crisis. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of COVID-19. Subversion of host protein synthesis is a common strategy that pathogenic viruses use to replicate and propagate in their host. In this study, we show that SARS-CoV-2 is able to shut down host protein synthesis and that SARS-CoV-2 nonstructural protein NSP14 exerts this activity. We show that the translation inhibition activity of NSP14 is conserved in human coronaviruses. NSP14 is required for virus replication through contribution of its exoribonuclease (ExoN) and N7-methyltransferase (N7-MTase) activities. Mutations in the ExoN or N7-MTase active sites of SARS-CoV-2 NSP14 abolish its translation inhibition activity. In addition, we show that the formation of NSP14−NSP10 complex enhances translation inhibition executed by NSP14. Consequently, the translational shutdown by NSP14 abolishes the type I interferon (IFN-I)-dependent induction of interferon-stimulated genes (ISGs). Together, we find that SARS-CoV-2 shuts down host innate immune responses via a translation inhibitor, providing insights into the pathogenesis of SARS-CoV-2.

scholarly journals A novel vibriophage exhibits inhibitory activity against host protein synthesis machinery

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Khrongkhwan Thammatinna ◽  
MacKennon E. Egan ◽  
Htut Htut Htoo ◽  
Kanika Khanna ◽  
Joseph Sugie ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Inhibitory Activity ◽  
Host Protein ◽  
Protein Synthesis Machinery ◽  
Host Protein Synthesis
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