Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication
Yang, Z.; Johnson, B. A.; Meliopoulos, V. A.; Ju, X.; Zhang, P.; Hughes, M. P.; Wu, J.; Koreski, K. P.; Chang, T.-C.; Wu, G.; Hixon, J.; Duffner, J.; Wong, K.; Lemieux, R.; Lokugamage, K. G.; Alvardo, R. E.; Crocquet-Valdes, P. A.; Walker, D. H.; Plante, K. S.; Plante, J. A.; Weaver, S. C.; Kim, H. J.; Meyers, R.; Schultz-Cherry, S.; Ding, Q.; Menachery, V. D.; Taylor, J. P.
Show abstract
G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. G3BP1/2 are prominent interactors of the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the functional consequences of the G3BP1-N interaction in the context of viral infection remain unclear. Here we used structural and biochemical analyses to define the residues required for G3BP1-N interaction, followed by structure-guided mutagenesis of G3BP1 and N to selectively and reciprocally disrupt their interaction. We found that mutation of F17 within the N protein led to selective loss of interaction with G3BP1 and consequent failure of the N protein to disrupt stress granule assembly. Introduction of SARS-CoV-2 bearing an F17A mutation resulted in a significant decrease in viral replication and pathogenesis in vivo, indicating that the G3BP1-N interaction promotes infection by suppressing the ability of G3BP1 to form stress granules.
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