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The SARS-CoV-2 protein NSP2 impairs the microRNA-induced silencing capacity of human cells

Limei Zou, Clara Moch, Marc Graille, View ORCID ProfileClément Chapat
doi: https://doi.org/10.1101/2022.01.25.477753
Limei Zou
1Laboratoire de Biologie Structurale de la Cellule (BIOC), CNRS, Ecole polytechnique, IP Paris. F-91128 Palaiseau, France
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Clara Moch
1Laboratoire de Biologie Structurale de la Cellule (BIOC), CNRS, Ecole polytechnique, IP Paris. F-91128 Palaiseau, France
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Marc Graille
1Laboratoire de Biologie Structurale de la Cellule (BIOC), CNRS, Ecole polytechnique, IP Paris. F-91128 Palaiseau, France
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Clément Chapat
1Laboratoire de Biologie Structurale de la Cellule (BIOC), CNRS, Ecole polytechnique, IP Paris. F-91128 Palaiseau, France
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  • ORCID record for Clément Chapat
  • For correspondence: clement.chapat@cnrs.fr
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Abstract

The coronavirus SARS-CoV-2 is the cause of the ongoing pandemic of COVID-19. Given the absence of effective treatments against SARS-CoV-2, there is an urgent need for a molecular understanding of how the virus influences the machineries of the host cell. The SARS-CoV-2 generates 16 Non-Structural Proteins (NSPs) through proteolytic cleavage of a large precursor protein. In the present study, we focused our attention on the SARS-CoV-2 protein NSP2, whose role in the viral pathogenicity is poorly understood. Recent proteomic studies shed light on the capacity of NSP2 to bind the 4EHP-GIGYF2 complex, a key factor involved in microRNA-mediated silencing of gene expression in human cells. In order to gain a better understanding of the function of NSP2, we attempted to identify the molecular basis of its interaction with 4EHP-GIGYF2. Our data demonstrate that NSP2 physically associates with the endogenous 4EHP-GIGYF2 complex in the cytoplasm. Using co-immunoprecipitation and in vitro interaction assays, we identified both 4EHP and a central segment in GIGYF2 as binding sites for NSP2. We also provide functional evidence that NSP2 impairs the function of GIGYF2 in mediating mRNA silencing using reporter-based assays, thus leading to a reduced activity of microRNAs. Altogether, these data reveal the profound impact of NSP2 on the post-transcriptional silencing of gene expression in human cells, pointing out 4EHP-GIGYF2 targeting as a possible strategy of SARS-CoV-2 to take over the silencing machinery and to suppress host defenses.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 26, 2022.
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The SARS-CoV-2 protein NSP2 impairs the microRNA-induced silencing capacity of human cells
Limei Zou, Clara Moch, Marc Graille, Clément Chapat
bioRxiv 2022.01.25.477753; doi: https://doi.org/10.1101/2022.01.25.477753
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The SARS-CoV-2 protein NSP2 impairs the microRNA-induced silencing capacity of human cells
Limei Zou, Clara Moch, Marc Graille, Clément Chapat
bioRxiv 2022.01.25.477753; doi: https://doi.org/10.1101/2022.01.25.477753

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