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Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen

Author

Listed:
  • Alice Mac Kain

    (Université de Paris Cité)

  • Ghizlane Maarifi

    (, Université de Montpellier, CNRS)

  • Sophie-Marie Aicher

    (Université de Paris Cité)

  • Nathalie Arhel

    (, Université de Montpellier, CNRS)

  • Artem Baidaliuk

    (Institut Pasteur, G5 Evolutionary genomics of RNA viruses)

  • Sandie Munier

    (Université de Paris Cité
    CNR Virus des infections respiratoires)

  • Flora Donati

    (Université de Paris Cité
    CNR Virus des infections respiratoires)

  • Thomas Vallet

    (Université de Paris Cité)

  • Quang Dinh Tran

    (Université de Paris Cité)

  • Alexandra Hardy

    (Université de Paris Cité)

  • Maxime Chazal

    (Université de Paris Cité)

  • Françoise Porrot

    (Université de Paris Cité)

  • Molly OhAinle

    (Fred Hutchinson Cancer Research Center)

  • Jared Carlson-Stevermer

    (Synthego Corporation)

  • Jennifer Oki

    (Synthego Corporation)

  • Kevin Holden

    (Synthego Corporation)

  • Gert Zimmer

    (University of Bern)

  • Etienne Simon-Lorière

    (Institut Pasteur, G5 Evolutionary genomics of RNA viruses)

  • Timothée Bruel

    (Université de Paris Cité)

  • Olivier Schwartz

    (Université de Paris Cité)

  • Sylvie van der Werf

    (Université de Paris Cité
    CNR Virus des infections respiratoires)

  • Nolwenn Jouvenet

    (Université de Paris Cité)

  • Sébastien Nisole

    (, Université de Montpellier, CNRS)

  • Marco Vignuzzi

    (Université de Paris Cité)

  • Ferdinand Roesch

    (Université de Paris Cité
    UMR 1282 ISP, INRAE Centre Val de Loire)

Abstract

Interferon restricts SARS-CoV-2 replication in cell culture, but only a handful of Interferon Stimulated Genes with antiviral activity against SARS-CoV-2 have been identified. Here, we describe a functional CRISPR/Cas9 screen aiming at identifying SARS-CoV-2 restriction factors. We identify DAXX, a scaffold protein residing in PML nuclear bodies known to limit the replication of DNA viruses and retroviruses, as a potent inhibitor of SARS-CoV-2 and SARS-CoV replication in human cells. Basal expression of DAXX is sufficient to limit the replication of SARS-CoV-2, and DAXX over-expression further restricts infection. DAXX restricts an early, post-entry step of the SARS-CoV-2 life cycle. DAXX-mediated restriction of SARS-CoV-2 is independent of the SUMOylation pathway but dependent on its D/E domain, also necessary for its protein-folding activity. SARS-CoV-2 infection triggers the re-localization of DAXX to cytoplasmic sites and promotes its degradation. Mechanistically, this process is mediated by the viral papain-like protease (PLpro) and the proteasome. Together, these results demonstrate that DAXX restricts SARS-CoV-2, which in turn has evolved a mechanism to counteract its action.

Suggested Citation

  • Alice Mac Kain & Ghizlane Maarifi & Sophie-Marie Aicher & Nathalie Arhel & Artem Baidaliuk & Sandie Munier & Flora Donati & Thomas Vallet & Quang Dinh Tran & Alexandra Hardy & Maxime Chazal & François, 2022. "Identification of DAXX as a restriction factor of SARS-CoV-2 through a CRISPR/Cas9 screen," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30134-9
    DOI: 10.1038/s41467-022-30134-9
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    References listed on IDEAS

    as
    1. Liangqian Huang & Trisha Agrawal & Guixin Zhu & Sixiang Yu & Liming Tao & JiaBei Lin & Ronen Marmorstein & James Shorter & Xiaolu Yang, 2021. "DAXX represents a new type of protein-folding enabler," Nature, Nature, vol. 597(7874), pages 132-137, September.
    2. Alexis J. Combes & Tristan Courau & Nicholas F. Kuhn & Kenneth H. Hu & Arja Ray & William S. Chen & Nayvin W. Chew & Simon J. Cleary & Divyashree Kushnoor & Gabriella C. Reeder & Alan Shen & Jessica T, 2021. "Global absence and targeting of protective immune states in severe COVID-19," Nature, Nature, vol. 591(7848), pages 124-130, March.
    3. Donghyuk Shin & Rukmini Mukherjee & Diana Grewe & Denisa Bojkova & Kheewoong Baek & Anshu Bhattacharya & Laura Schulz & Marek Widera & Ahmad Reza Mehdipour & Georg Tascher & Paul P. Geurink & Alexande, 2020. "Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity," Nature, Nature, vol. 587(7835), pages 657-662, November.
    4. Alexis J. Combes & Tristan Courau & Nicholas F. Kuhn & Kenneth H. Hu & Arja Ray & William S. Chen & Nayvin W. Chew & Simon J. Cleary & Divyashree Kushnoor & Gabriella C. Reeder & Alan Shen & Jessica T, 2021. "Publisher Correction: Global absence and targeting of protective immune states in severe COVID-19," Nature, Nature, vol. 596(7872), pages 8-8, August.
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