Phosphorylation toggles the SARS-CoV-2 nucleocapsid protein between two membrane-associated condensate states

Bruna Favetta, Huan Wang, Jasmine Cubuk, Arjun Singh, Mayur Barai, Cesar Ramirez, Haiyan Zheng, Adam J. Gormley, N. Sanjeeva Murthy, Gregory Dignon, Andrea Soranno, Zheng Shi and Benjamin S. Schuster ()
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Bruna Favetta: The State University of New Jersey
Huan Wang: The State University of New Jersey
Jasmine Cubuk: Washington University in St Louis
Arjun Singh: The State University of New Jersey
Mayur Barai: The State University of New Jersey
Cesar Ramirez: The State University of New Jersey
Haiyan Zheng: The State University of New Jersey
Adam J. Gormley: The State University of New Jersey
N. Sanjeeva Murthy: The State University of New Jersey
Gregory Dignon: The State University of New Jersey
Andrea Soranno: Washington University in St Louis
Zheng Shi: The State University of New Jersey
Benjamin S. Schuster: The State University of New Jersey

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract The Nucleocapsid protein (N) of SARS-CoV-2 plays a critical role in the viral lifecycle by regulating RNA replication and by packaging the viral genome. N and RNA phase separate to form condensates that may be important for these functions. Both functions occur at membrane surfaces, but how N toggles between these two membrane-associated functional states is unclear. Here, we reveal that phosphorylation switches how N condensates interact with membranes, in part by modulating condensate material properties. Our studies also show that phosphorylation alters N’s interaction with viral membrane proteins. We gain mechanistic insight through structural analysis and molecular simulations, which suggest phosphorylation induces a conformational change in N that softens condensate material properties. Together, our findings identify membrane association as a key feature of N condensates and provide mechanistic insights into the regulatory role of phosphorylation. Understanding this mechanism suggests potential therapeutic targets for COVID infection.

Date: 2025
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DOI: 10.1038/s41467-025-62922-4

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