Genomic RNA Elements Drive Phase Separation of the SARS-CoV-2 Nucleocapsid

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  • Iserman, C.
    • Affiliation: College of Arts and Sciences, Department of Biology
  • Roden, C.A.
    • Affiliation: College of Arts and Sciences, Department of Biology
  • Boerneke, M.A.
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • Sealfon, R.S.G.
    • Other Affiliation: Flatiron Institute
  • McLaughlin, G.A.
    • Affiliation: College of Arts and Sciences, Department of Biology
  • Jungreis, I.
    • Other Affiliation: Broad Institute of MIT and Harvard
  • Fritch, E.J.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Hou, Y.J.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Ekena, J.
    • Affiliation: College of Arts and Sciences, Department of Biology
  • Weidmann, C.A.
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • Theesfeld, C.L.
    • Other Affiliation: Princeton University
  • Kellis, M.
    • Other Affiliation: Broad Institute of MIT and Harvard
  • Troyanskaya, O.G.
    • Other Affiliation: Flatiron Institute
  • Baric, R.S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Sheahan, T.P.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Weeks, K.M.
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • Gladfelter, A.S.
    • Affiliation: College of Arts and Sciences, Department of Biology
Abstract
  • We report that the SARS-CoV-2 nucleocapsid protein (N-protein) undergoes liquid-liquid phase separation (LLPS) with viral RNA. N-protein condenses with specific RNA genomic elements under physiological buffer conditions and condensation is enhanced at human body temperatures (33°C and 37°C) and reduced at room temperature (22°C). RNA sequence and structure in specific genomic regions regulate N-protein condensation while other genomic regions promote condensate dissolution, potentially preventing aggregation of the large genome. At low concentrations, N-protein preferentially crosslinks to specific regions characterized by single-stranded RNA flanked by structured elements and these features specify the location, number, and strength of N-protein binding sites (valency). Liquid-like N-protein condensates form in mammalian cells in a concentration-dependent manner and can be altered by small molecules. Condensation of N-protein is RNA sequence and structure specific, sensitive to human body temperature, and manipulatable with small molecules, and therefore presents a screenable process for identifying antiviral compounds effective against SARS-CoV-2.
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  • Article
Rights statement
  • In Copyright
Journal title
  • Molecular Cell
Journal volume
  • 80
Journal issue
  • 6
Page start
  • 1078
Page end
  • 1.09E+09
Language
  • English
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  • Publisher
ISSN
  • 1097-2765
Publisher
  • Cell Press

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