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

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.

Cited by papers we hold 11

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• Nucleocapsid mutations in SARS-CoV-2 augment replication and pathogenesis · 2022
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• RNA-induced liquid phase separation of SARS-CoV-2 nucleocapsid protein facilitates NF-κB hyper-activation and inflammation · 2021
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• The Integral Role of RNA in Stress Granule Formation and Function · 2021
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• Liquid–liquid phase separation in human health and diseases · 2021
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• The SARS-CoV-2 nucleocapsid protein is dynamic, disordered, and phase separates with RNA · 2021
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• Correlative multi-scale cryo-imaging unveils SARS-CoV-2 assembly and egress · 2021
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• SARS‐CoV‐2 nucleocapsid protein phase‐separates with RNA and with human hnRNPs · 2020
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