Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication and pathogenicity

Zemin Yang, Bryan A. Johnson, Victoria A. Meliopoulos, Xiaohui Ju, Peipei Zhang, Michael P. Hughes, Jinjun Wu, Kaitlin P. Koreski, Jemma E. Clary, Ti Cheng Chang, Gang Wu, Jeff Hixon, Jay Duffner, Kathy Wong, Rene Lemieux, Kumari G. Lokugamage, R. Elias Alvarado, Patricia A. Crocquet-Valdes, David H. Walker, Kenneth S. PlanteJessica Plante, Scott C. Weaver, Hong Joo Kim, Rachel Meyers, Stacey Schultz-Cherry, Qiang Ding, Vineet D. Menachery, J. Paul Taylor

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

G3BP1/2 are paralogous proteins that promote stress granule formation in response to cellular stresses, including viral infection. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibits stress granule assembly and interacts with G3BP1/2 via an ITFG motif, including residue F17, in the N protein. Prior studies examining the impact of the G3PB1-N interaction on SARS-CoV-2 replication have produced inconsistent findings, and the role of this interaction in pathogenesis is unknown. Here, we use structural and biochemical analyses to define the residues required for G3BP1-N interaction and structure-guided mutagenesis to selectively disrupt this interaction. We find that N-F17A mutation causes highly specific loss of interaction with G3BP1/2. SARS-CoV-2 N-F17A fails to inhibit stress granule assembly in cells, has decreased viral replication, and causes decreased pathology in vivo. Further mechanistic studies indicate that the N-F17-mediated G3BP1-N interaction promotes infection by limiting sequestration of viral genomic RNA (gRNA) into stress granules.

Original languageEnglish (US)
Article number113965
JournalCell Reports
Volume43
Issue number3
DOIs
StatePublished - Mar 26 2024

Keywords

  • CP: Microbiology
  • G3BP
  • NTF2L domain
  • SARS-CoV-2 replication and pathogenesis
  • host-pathogen interaction
  • nucleocapsid protein
  • stress granule
  • vRNA sequestration

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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