SARS-CoV-2 N protein recruits G3BP to double membrane vesicles to promote translation of viral mRNAs

Siwen Long, Mykhailo Guzyk, Laura Perez Vidakovics, Xiao Han, Renhua Sun, Megan Wang, Marc D. Panas, Egon Urgard, Jonathan M. Coquet, Andres Merits, Adnane Achour and Gerald M. McInerney ()
Additional contact information
Siwen Long: Karolinska Institutet
Mykhailo Guzyk: Karolinska Institutet
Laura Perez Vidakovics: Karolinska Institutet
Xiao Han: Karolinska Institute Solna
Renhua Sun: Karolinska Institute Solna
Megan Wang: Karolinska Institutet
Marc D. Panas: Karolinska Institutet
Egon Urgard: University of Copenhagen
Jonathan M. Coquet: Karolinska Institutet
Andres Merits: University of Tartu
Adnane Achour: Karolinska Institute Solna
Gerald M. McInerney: Karolinska Institutet

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Ras-GTPase-activating protein SH3-domain-binding proteins (G3BP) are critical for the formation of stress granules (SGs) through their RNA- and ribosome-binding properties. SARS-CoV-2 nucleocapsid (N) protein exhibits strong binding affinity for G3BP and inhibits infection-induced SG formation soon after infection. To study the impact of the G3BP-N interaction on viral replication and pathogenesis in detail, we generated a mutant SARS-CoV-2 (RATA) that specifically lacks the G3BP-binding motif in the N protein. RATA triggers a stronger and more persistent SG response in infected cells, showing reduced replication across various cell lines, and greatly reduced pathogenesis in K18-hACE2 transgenic mice. At early times of infection, G3BP and WT N protein strongly colocalise with dsRNA and with non-structural protein 3 (nsp3), a component of the pore complex in double membrane vesicles (DMVs) from which nascent viral RNA emerges. Furthermore, G3BP-N complexes promote highly localized translation of viral mRNAs in the immediate vicinity of the DMVs and thus contribute to efficient viral gene expression and replication. In contrast, G3BP is absent from the DMVs in cells infected with RATA and translation of viral mRNAs is less efficient. This work provides a fuller understanding of the multifunctional roles of G3BP in SARS-CoV-2 infection.

Date: 2024
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DOI: 10.1038/s41467-024-54996-3

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