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SARS-CoV-2 Nsp1 regulates translation start site fidelity to promote infection

A better mechanistic understanding of virus-host interactions can help reveal vulnerabilities and identify opportunities for therapeutic interventions. Of particular interest are essential interactions that enable production of viral proteins, as those could target an early step in the virus lifecyc...

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Autores principales: Aviner, Ranen, Lidsky, Peter V, Xiao, Yinghong, Tasseto, Michel, Zhang, Lichao, McAlpine, Patrick L, Elias, Joshua, Frydman, Judith, Andino, Raul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350044/
https://www.ncbi.nlm.nih.gov/pubmed/37461541
http://dx.doi.org/10.1101/2023.07.05.547902
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author Aviner, Ranen
Lidsky, Peter V
Xiao, Yinghong
Tasseto, Michel
Zhang, Lichao
McAlpine, Patrick L
Elias, Joshua
Frydman, Judith
Andino, Raul
author_facet Aviner, Ranen
Lidsky, Peter V
Xiao, Yinghong
Tasseto, Michel
Zhang, Lichao
McAlpine, Patrick L
Elias, Joshua
Frydman, Judith
Andino, Raul
author_sort Aviner, Ranen
collection PubMed
description A better mechanistic understanding of virus-host interactions can help reveal vulnerabilities and identify opportunities for therapeutic interventions. Of particular interest are essential interactions that enable production of viral proteins, as those could target an early step in the virus lifecycle. Here, we use subcellular proteomics, ribosome profiling analyses and reporter assays to detect changes in polysome composition and protein synthesis during SARS-CoV-2 (CoV2) infection. We identify specific translation factors and molecular chaperones whose inhibition impairs infectious particle production without major toxicity to the host. We find that CoV2 non-structural protein Nsp1 selectively enhances virus translation through functional interactions with initiation factor EIF1A. When EIF1A is depleted, more ribosomes initiate translation from an upstream CUG start codon, inhibiting translation of non-structural genes and reducing viral titers. Together, our work describes multiple dependencies of CoV2 on host biosynthetic networks and identifies druggable targets for potential antiviral development.
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spelling pubmed-103500442023-07-17 SARS-CoV-2 Nsp1 regulates translation start site fidelity to promote infection Aviner, Ranen Lidsky, Peter V Xiao, Yinghong Tasseto, Michel Zhang, Lichao McAlpine, Patrick L Elias, Joshua Frydman, Judith Andino, Raul bioRxiv Article A better mechanistic understanding of virus-host interactions can help reveal vulnerabilities and identify opportunities for therapeutic interventions. Of particular interest are essential interactions that enable production of viral proteins, as those could target an early step in the virus lifecycle. Here, we use subcellular proteomics, ribosome profiling analyses and reporter assays to detect changes in polysome composition and protein synthesis during SARS-CoV-2 (CoV2) infection. We identify specific translation factors and molecular chaperones whose inhibition impairs infectious particle production without major toxicity to the host. We find that CoV2 non-structural protein Nsp1 selectively enhances virus translation through functional interactions with initiation factor EIF1A. When EIF1A is depleted, more ribosomes initiate translation from an upstream CUG start codon, inhibiting translation of non-structural genes and reducing viral titers. Together, our work describes multiple dependencies of CoV2 on host biosynthetic networks and identifies druggable targets for potential antiviral development. Cold Spring Harbor Laboratory 2023-07-06 /pmc/articles/PMC10350044/ /pubmed/37461541 http://dx.doi.org/10.1101/2023.07.05.547902 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Aviner, Ranen
Lidsky, Peter V
Xiao, Yinghong
Tasseto, Michel
Zhang, Lichao
McAlpine, Patrick L
Elias, Joshua
Frydman, Judith
Andino, Raul
SARS-CoV-2 Nsp1 regulates translation start site fidelity to promote infection
title SARS-CoV-2 Nsp1 regulates translation start site fidelity to promote infection
title_full SARS-CoV-2 Nsp1 regulates translation start site fidelity to promote infection
title_fullStr SARS-CoV-2 Nsp1 regulates translation start site fidelity to promote infection
title_full_unstemmed SARS-CoV-2 Nsp1 regulates translation start site fidelity to promote infection
title_short SARS-CoV-2 Nsp1 regulates translation start site fidelity to promote infection
title_sort sars-cov-2 nsp1 regulates translation start site fidelity to promote infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350044/
https://www.ncbi.nlm.nih.gov/pubmed/37461541
http://dx.doi.org/10.1101/2023.07.05.547902
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