tetano
Editor, Senior Moderator
Cell Rep
. 2024 Mar 14;43(3):113965.
doi: 10.1016/j.celrep.2024.113965. Online ahead of print. Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication and pathogenicity
Zemin Yang[SUP] 1 [/SUP], Bryan A Johnson[SUP] 2 [/SUP], Victoria A Meliopoulos[SUP] 3 [/SUP], Xiaohui Ju[SUP] 4 [/SUP], Peipei Zhang[SUP] 5 [/SUP], Michael P Hughes[SUP] 5 [/SUP], Jinjun Wu[SUP] 1 [/SUP], Kaitlin P Koreski[SUP] 5 [/SUP], Jemma E Clary[SUP] 5 [/SUP], Ti-Cheng Chang[SUP] 6 [/SUP], Gang Wu[SUP] 6 [/SUP], Jeff Hixon[SUP] 7 [/SUP], Jay Duffner[SUP] 7 [/SUP], Kathy Wong[SUP] 7 [/SUP], Rene Lemieux[SUP] 7 [/SUP], Kumari G Lokugamage[SUP] 8 [/SUP], R Elias Alvarado[SUP] 8 [/SUP], Patricia A Crocquet-Valdes[SUP] 9 [/SUP], David H Walker[SUP] 9 [/SUP], Kenneth S Plante[SUP] 10 [/SUP], Jessica A Plante[SUP] 10 [/SUP], Scott C Weaver[SUP] 11 [/SUP], Hong Joo Kim[SUP] 5 [/SUP], Rachel Meyers[SUP] 7 [/SUP], Stacey Schultz-Cherry[SUP] 3 [/SUP], Qiang Ding[SUP] 4 [/SUP], Vineet D Menachery[SUP] 12 [/SUP], J Paul Taylor[SUP] 13 [/SUP]
Affiliations
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.
Keywords: CP: Microbiology; G3BP; NTF2L domain; SARS-CoV-2 replication and pathogenesis; host-pathogen interaction; nucleocapsid protein; stress granule; vRNA sequestration.
. 2024 Mar 14;43(3):113965.
doi: 10.1016/j.celrep.2024.113965. Online ahead of print. Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication and pathogenicity
Zemin Yang[SUP] 1 [/SUP], Bryan A Johnson[SUP] 2 [/SUP], Victoria A Meliopoulos[SUP] 3 [/SUP], Xiaohui Ju[SUP] 4 [/SUP], Peipei Zhang[SUP] 5 [/SUP], Michael P Hughes[SUP] 5 [/SUP], Jinjun Wu[SUP] 1 [/SUP], Kaitlin P Koreski[SUP] 5 [/SUP], Jemma E Clary[SUP] 5 [/SUP], Ti-Cheng Chang[SUP] 6 [/SUP], Gang Wu[SUP] 6 [/SUP], Jeff Hixon[SUP] 7 [/SUP], Jay Duffner[SUP] 7 [/SUP], Kathy Wong[SUP] 7 [/SUP], Rene Lemieux[SUP] 7 [/SUP], Kumari G Lokugamage[SUP] 8 [/SUP], R Elias Alvarado[SUP] 8 [/SUP], Patricia A Crocquet-Valdes[SUP] 9 [/SUP], David H Walker[SUP] 9 [/SUP], Kenneth S Plante[SUP] 10 [/SUP], Jessica A Plante[SUP] 10 [/SUP], Scott C Weaver[SUP] 11 [/SUP], Hong Joo Kim[SUP] 5 [/SUP], Rachel Meyers[SUP] 7 [/SUP], Stacey Schultz-Cherry[SUP] 3 [/SUP], Qiang Ding[SUP] 4 [/SUP], Vineet D Menachery[SUP] 12 [/SUP], J Paul Taylor[SUP] 13 [/SUP]
Affiliations
- PMID: 38492217
- DOI: 10.1016/j.celrep.2024.113965
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.
Keywords: CP: Microbiology; G3BP; NTF2L domain; SARS-CoV-2 replication and pathogenesis; host-pathogen interaction; nucleocapsid protein; stress granule; vRNA sequestration.