Interaction between host G3BP and viral nucleocapsid protein regulates SARS-CoV-2 replication and pathogenicity.
Autor: | Yang Z; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA; Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA., Johnson BA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, USA; Center for Tropical Diseases, University of Texas Medical Branch, Galveston, TX, USA., Meliopoulos VA; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA., Ju X; School of Medicine, Tsinghua University, Beijing, China., Zhang P; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Hughes MP; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Wu J; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA; Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN, USA., Koreski KP; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Clary JE; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Chang TC; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA., Wu G; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA., Hixon J; Faze Medicines, Cambridge, MA, USA., Duffner J; Faze Medicines, Cambridge, MA, USA., Wong K; Faze Medicines, Cambridge, MA, USA., Lemieux R; Faze Medicines, Cambridge, MA, USA., Lokugamage KG; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA., Alvarado RE; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA., Crocquet-Valdes PA; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA., Walker DH; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA., Plante KS; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA., Plante JA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA., Weaver SC; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA., Kim HJ; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Meyers R; Faze Medicines, Cambridge, MA, USA., Schultz-Cherry S; Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, USA., Ding Q; School of Medicine, Tsinghua University, Beijing, China., Menachery VD; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA. Electronic address: vimenach@utmb.edu., Taylor JP; Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA. Electronic address: jpaul.taylor@stjude.org. |
---|---|
Jazyk: | angličtina |
Zdroj: | Cell reports [Cell Rep] 2024 Mar 26; Vol. 43 (3), pp. 113965. Date of Electronic Publication: 2024 Mar 15. |
DOI: | 10.1016/j.celrep.2024.113965 |
Abstrakt: | 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. Competing Interests: Declaration of interests J.P.T. is a consultant for Nido Biosciences. V.D.M. has filed a patent on the reverse genetic system and reporter SARS-CoV-2. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
Externí odkaz: |