The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein

Shan Lu, Qiaozhen Ye, Digvijay Singh, Yong Cao, Jolene K. Diedrich, John R. Yates, Elizabeth Villa, Don W. Cleveland () and Kevin D. Corbett ()
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Shan Lu: University of California, San Diego
Qiaozhen Ye: University of California, San Diego
Digvijay Singh: University of California San Diego
Yong Cao: National Institute of Biological Sciences
Jolene K. Diedrich: The Scripps Research Institute
John R. Yates: The Scripps Research Institute
Elizabeth Villa: University of California San Diego
Don W. Cleveland: University of California, San Diego
Kevin D. Corbett: University of California, San Diego

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract The multifunctional nucleocapsid (N) protein in SARS-CoV-2 binds the ~30 kb viral RNA genome to aid its packaging into the 80–90 nm membrane-enveloped virion. The N protein is composed of N-terminal RNA-binding and C-terminal dimerization domains that are flanked by three intrinsically disordered regions. Here we demonstrate that the N protein’s central disordered domain drives phase separation with RNA, and that phosphorylation of an adjacent serine/arginine rich region modulates the physical properties of the resulting condensates. In cells, N forms condensates that recruit the stress granule protein G3BP1, highlighting a potential role for N in G3BP1 sequestration and stress granule inhibition. The SARS-CoV-2 membrane (M) protein independently induces N protein phase separation, and three-component mixtures of N + M + RNA form condensates with mutually exclusive compartments containing N + M or N + RNA, including annular structures in which the M protein coats the outside of an N + RNA condensate. These findings support a model in which phase separation of the SARS-CoV-2 N protein contributes both to suppression of the G3BP1-dependent host immune response and to packaging genomic RNA during virion assembly.

Date: 2021
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DOI: 10.1038/s41467-020-20768-y

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