Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.06.29.546885v1?rss=1

Authors: 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.

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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