Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression

Zhang, Ke; Miorin, Lisa; Makio, Tadashi; Dehghan, Ishmael; Gao, Shengyan; Xie, Yihu; Zhong, Hualin; Esparza, Matthew A.; Kehrer, Thomas; Kumar, Anil; Hobman, Tom C.; Ptak, Christopher; Gao, Boning; Minna, John D.; Chen, Zhijian; García‐Sastre, Adolfo; Ren, Yi; Wozniak, Richard W.; Fontoura, Beatriz M. A.

doi:10.1126/sciadv.abe7386

Cited by 182 publications

(220 citation statements)

References 34 publications

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“…While a previous study has established the crucial role played by N in viral genome processing and nucleocapsid assembly (Carlson et al, 2020), to the best of our knowledge there have been no prior reports specifically highlighting its ability to elevate lentiviral spike pseudovirus infectivity. It bears mentioning that similar to existent reports (Min et al, 2020;Schubert et al, 2020;Thoms et al, 2020;Lapointe et al, 2021;Zhang et al, 2021), the Nsp1 protein presumably exerts a detrimental effect on the host cell's protein translation, as indicated by the almost imperceptible extent of infectivity observed in its case (Figure 2A).…”

Section: Discussionsupporting

confidence: 83%

SARS CoV-2 Nucleoprotein Enhances the Infectivity of Lentiviral Spike Particles

Mishra

Sreepadmanabh

Ramdas

et al. 2021

Front. Cell. Infect. Microbiol.

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The establishment of SARS CoV-2 spike-pseudotyped lentiviral (LV) systems has enabled the rapid identification of entry inhibitors and neutralizing agents, alongside allowing for the study of this emerging pathogen in BSL-2 level facilities. While such frameworks recapitulate the cellular entry process in ACE2+ cells, they are largely unable to factor in supplemental contributions by other SARS CoV-2 genes. To address this, we performed an unbiased ORF screen and identified the nucleoprotein (N) as a potent enhancer of spike-pseudotyped LV particle infectivity. We further demonstrate that the spike protein is better enriched in virions when the particles are produced in the presence of N protein. This enrichment of spike renders LV particles more infectious as well as less vulnerable to the neutralizing effects of a human IgG-Fc fused ACE2 microbody. Importantly, this improvement in infectivity is observed with both wild-type spike protein as well as the D614G mutant. Our results hold important implications for the design and interpretation of similar LV pseudotyping-based studies.

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Section: Discussionsupporting

confidence: 83%

SARS CoV-2 Nucleoprotein Enhances the Infectivity of Lentiviral Spike Particles

Mishra

Sreepadmanabh

Ramdas

et al. 2021

Front. Cell. Infect. Microbiol.

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“…A likely explanation for the export block is that widespread cytosolic mRNA degradation leads to re-localization of numerous RNA binding proteins to the nucleus (Khong and Parker 2020, RNA;Burke et al, 2019;Kumar and Glaunsinger, 2010), which would then compete for the binding of export factors to mRNAs. Consistent with that hypothesis, overexpression of the mRNA export factor NXF1 (Nuclear RNA Export Factor 1) has been suggested to overcome an mRNA export block due to Nsp1 binding to NXF1 (Zhang et al, 2021). However, we anticipate that Nsp1 binding to NXF1 would not be required for inhibition of mRNA export in SARS-CoV-2 infected cells since anytime mRNAs are degraded via RNase L activation, which happens in SARS-CoV-2 infections (Fig.…”

Section: Discussionsupporting

confidence: 73%

Rapid decay of host basal mRNAs during SARS-CoV-2 infection perturbs host antiviral mRNA biogenesis and export

LAs

Perera

et al. 2021

Preprint

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A key feature of the mammalian innate immune response to viral infection is the transcriptional induction of interferon (IFN) genes, which encode for secreted proteins that prime the antiviral response and limit viral replication and dissemination. A hallmark of severe COVID-19 disease caused by SARS-CoV-2 is the low presence of IFN proteins in patient serum despite elevated levels of IFN-encoding mRNAs, indicative of post-transcriptional inhibition of IFN protein production. Herein, we show SARS-CoV-2 infection limits type I and type III IFN biogenesis by preventing the release of mRNA from their sites of transcription and/or triggering their nuclear degradation. In addition, SARS-CoV-2 infection inhibits nuclear-cytoplasmic transport of IFN mRNAs as a consequence of widespread cytosolic mRNA degradation mediated by both activation of the host antiviral endoribonuclease, RNase L, and by the SARS-CoV-2 protein, Nsp1. These findings argue that inhibition of host and/or viral Nsp1-mediated mRNA decay, as well as IFN treatments, may reduce viral-associated pathogenesis by promoting the innate immune response.

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“…Secondly, the binding of Nsp1 to the ribosome directs the endonucleolytic division and host mRNA degradation [ 6 ]. Nsp1 of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression [ 12 ]. In addition, Nsp1 could be able to reduce cellular translation considerably; however, remaining ribosomes would still be able to translate viral mRNAs with high efficiency [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

A computational approach for rational discovery of inhibitors for non-structural protein 1 of SARS-CoV-2

Singh

Bhardwaj

Das

et al. 2021

Computers in Biology and Medicine

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Background Non-structural protein 1 (Nsp1), a virulence agent of SARS-CoV-2, has emerged as an important target for drug discovery. Nsp1 shuts down the host gene function by associating with the 40S ribosomal subunit. Methods Molecular interactions, drug-likeness, physiochemical property predictions, and robust molecular dynamics (MD) simulations were employed to discover novel Nsp1 inhibitors. In this study, we evaluated a series of molecules based on the plant ( Cedrus deodara ) derived α,β,γ -Himachalenes scaffolds. Results The results obtained from estimated affinity and ligand efficiency suggested that BCH10, BCH15, BCH16, and BCH17 could act as potential inhibitors of Nsp1. Moreover, MD simulations comprising various MD driven time-dependent analyses and thermodynamic free energy calculations also suggested stable protein-ligand complexes and strong interactions with the binding site. Furthermore, the selected molecules passed drug likeliness parameters and the physiochemical property analysis showed acceptable bioactivity scores. Conclusion The structural parameters of dynamic simulations revealed that the reported molecules could act as lead compounds against SARS-CoV-2 Nsp1 protein.

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Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression

Cited by 182 publications

References 34 publications

SARS CoV-2 Nucleoprotein Enhances the Infectivity of Lentiviral Spike Particles

SARS CoV-2 Nucleoprotein Enhances the Infectivity of Lentiviral Spike Particles

Rapid decay of host basal mRNAs during SARS-CoV-2 infection perturbs host antiviral mRNA biogenesis and export

A computational approach for rational discovery of inhibitors for non-structural protein 1 of SARS-CoV-2

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