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Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates

Author

Listed:
  • Adriana Savastano

    (German Center for Neurodegenerative Diseases (DZNE))

  • Alain Ibáñez de Opakua

    (German Center for Neurodegenerative Diseases (DZNE))

  • Marija Rankovic

    (Max Planck Institute for Biophysical Chemistry)

  • Markus Zweckstetter

    (German Center for Neurodegenerative Diseases (DZNE)
    Max Planck Institute for Biophysical Chemistry)

Abstract

The etiologic agent of the Covid-19 pandemic is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral membrane of SARS-CoV-2 surrounds a helical nucleocapsid in which the viral genome is encapsulated by the nucleocapsid protein. The nucleocapsid protein of SARS-CoV-2 is produced at high levels within infected cells, enhances the efficiency of viral RNA transcription, and is essential for viral replication. Here, we show that RNA induces cooperative liquid–liquid phase separation of the SARS-CoV-2 nucleocapsid protein. In agreement with its ability to phase separate in vitro, we show that the protein associates in cells with stress granules, cytoplasmic RNA/protein granules that form through liquid-liquid phase separation and are modulated by viruses to maximize replication efficiency. Liquid–liquid phase separation generates high-density protein/RNA condensates that recruit the RNA-dependent RNA polymerase complex of SARS-CoV-2 providing a mechanism for efficient transcription of viral RNA. Inhibition of RNA-induced phase separation of the nucleocapsid protein by small molecules or biologics thus can interfere with a key step in the SARS-CoV-2 replication cycle.

Suggested Citation

  • Adriana Savastano & Alain Ibáñez de Opakua & Marija Rankovic & Markus Zweckstetter, 2020. "Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19843-1
    DOI: 10.1038/s41467-020-19843-1
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    Cited by:

    1. Sophie Marianne Korn & Karthikeyan Dhamotharan & Cy M. Jeffries & Andreas Schlundt, 2023. "The preference signature of the SARS-CoV-2 Nucleocapsid NTD for its 5’-genomic RNA elements," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Jiang Ren & Shuai Wang & Zhi Zong & Ting Pan & Sijia Liu & Wei Mao & Huizhe Huang & Xiaohua Yan & Bing Yang & Xin He & Fangfang Zhou & Long Zhang, 2024. "TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Mirren Charnley & Saba Islam & Guneet K. Bindra & Jeremy Engwirda & Julian Ratcliffe & Jiangtao Zhou & Raffaele Mezzenga & Mark D. Hulett & Kyunghoon Han & Joshua T. Berryman & Nicholas P. Reynolds, 2022. "Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. Einav Tayeb-Fligelman & Jeannette T. Bowler & Christen E. Tai & Michael R. Sawaya & Yi Xiao Jiang & Gustavo Garcia & Sarah L. Griner & Xinyi Cheng & Lukasz Salwinski & Liisa Lutter & Paul M. Seidler &, 2023. "Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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