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A genome-wide CRISPR/Cas9 knock-out screen identifies the DEAD box RNA helicase DDX42 as a broad antiviral inhibitor

Bonaventure Boris, Rebendenne Antoine, Garcia de Gracia Francisco, Tauziet Marine, McKellar Joe, Chaves Valadão Ana Luiza, Courgnaud Valérie, Bernard Eric, Briant Laurence, Gros Nathalie, Djilli Wassila, Arnaud-Arnould Mary, Parrinello Hugues, Rialle Stéphanie, Moncorgé Olivier, View ORCID ProfileGoujon Caroline
doi: https://doi.org/10.1101/2020.10.28.359356
Bonaventure Boris
1IRIM, CNRS, Université de Montpellier
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Rebendenne Antoine
1IRIM, CNRS, Université de Montpellier
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Garcia de Gracia Francisco
1IRIM, CNRS, Université de Montpellier
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Tauziet Marine
1IRIM, CNRS, Université de Montpellier
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McKellar Joe
1IRIM, CNRS, Université de Montpellier
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Chaves Valadão Ana Luiza
1IRIM, CNRS, Université de Montpellier
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Courgnaud Valérie
2IGMM, CNRS, Université de Montpellier
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Bernard Eric
1IRIM, CNRS, Université de Montpellier
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Briant Laurence
1IRIM, CNRS, Université de Montpellier
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Gros Nathalie
3CEMIPAI, CNRS, Université de Montpellier
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Djilli Wassila
1IRIM, CNRS, Université de Montpellier
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Arnaud-Arnould Mary
1IRIM, CNRS, Université de Montpellier
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Parrinello Hugues
4Montpellier GenomiX (MGX)
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Rialle Stéphanie
4Montpellier GenomiX (MGX)
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Moncorgé Olivier
1IRIM, CNRS, Université de Montpellier
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Goujon Caroline
1IRIM, CNRS, Université de Montpellier
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  • ORCID record for Goujon Caroline
  • For correspondence: caroline.goujon@irim.cnrs.fr
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Abstract

Genome-wide CRISPR/Cas9 knock-out genetic screens are powerful approaches to unravel new regulators of viral infections. With the aim of identifying new cellular inhibitors of HIV-1, we have developed a strategy in which we took advantage of the ability of type 1 interferon (IFN) to potently inhibit HIV-1 infection, in order to create a cellular environment hostile to viral replication. This approach led to the identification of the DEAD-box RNA helicase DDX42 as an intrinsic inhibitor of HIV-1. Depletion of endogenous DDX42 using siRNA or CRISPR/Cas9 knock-out increased HIV-1 infection, both in model cell lines and in physiological targets of HIV-1, primary CD4+ T cells and monocyte-derived macrophages (MDMs), and irrespectively of the IFN treatment. Similarly, the overexpression of a dominant-negative mutant of DDX42 positively impacted HIV-1 infection, whereas wild-type DDX42 overexpression potently inhibited HIV-1 infection. The positive impact of endogenous DDX42 depletion on HIV-1 infection was directly correlated to an increase in viral DNA accumulation. Interestingly, proximity ligation assays showed that DDX42, which can be mainly found in the nucleus but is also present in the cytoplasm, was in the close vicinity of HIV-1 Capsid during infection of primary monocyte-derived macrophages. Moreover, we show that DDX42 is also able to substantially decrease infection with other retroviruses and retrotransposition of long interspersed elements-1 (LINE-1). Finally, we reveal that DDX42 potently inhibits other pathogenic viruses, including Chikungunya virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

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. All rights reserved. No reuse allowed without permission.
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Posted October 28, 2020.
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A genome-wide CRISPR/Cas9 knock-out screen identifies the DEAD box RNA helicase DDX42 as a broad antiviral inhibitor
Bonaventure Boris, Rebendenne Antoine, Garcia de Gracia Francisco, Tauziet Marine, McKellar Joe, Chaves Valadão Ana Luiza, Courgnaud Valérie, Bernard Eric, Briant Laurence, Gros Nathalie, Djilli Wassila, Arnaud-Arnould Mary, Parrinello Hugues, Rialle Stéphanie, Moncorgé Olivier, Goujon Caroline
bioRxiv 2020.10.28.359356; doi: https://doi.org/10.1101/2020.10.28.359356
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A genome-wide CRISPR/Cas9 knock-out screen identifies the DEAD box RNA helicase DDX42 as a broad antiviral inhibitor
Bonaventure Boris, Rebendenne Antoine, Garcia de Gracia Francisco, Tauziet Marine, McKellar Joe, Chaves Valadão Ana Luiza, Courgnaud Valérie, Bernard Eric, Briant Laurence, Gros Nathalie, Djilli Wassila, Arnaud-Arnould Mary, Parrinello Hugues, Rialle Stéphanie, Moncorgé Olivier, Goujon Caroline
bioRxiv 2020.10.28.359356; doi: https://doi.org/10.1101/2020.10.28.359356

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