title: Human GBP1 does not localize to pathogen vacuoles but restricts Toxoplasma gondii.
abstract: Guanylate binding proteins (GBPs) are a family of large interferon-inducible GTPases that are transcriptionally upregulated upon infection with intracellular pathogens. Murine GBPs (mGBPs) including mGBP1 and 2 localize to and disrupt pathogen-containing vacuoles (PVs) resulting in the cell-autonomous clearing or innate immune detection of PV-resident pathogens. Human GBPs (hGBPs) are known to exert antiviral host defense and activate the NLRP3 inflammasome, but it is unclear whether hGBPs can directly recognize and control intravacuolar pathogens. Here, we report that endogenous or ectopically expressed hGBP1 fails to associate with PVs formed in human cells by the bacterial pathogens Chlamydia trachomatis or Salmonella typhimurium or the protozoan pathogen Toxoplasma gondii. While we find that hGBP1 expression has no discernible effect on intracellular replication of C. trachomatis and S. typhimurium, we observed enhanced early Toxoplasma replication in CRISPR hGBP1-deleted human epithelial cells. We thus identified a novel role for hGBP1 in cell-autonomous immunity that is independent of PV translocation, as observed for mGBPs. This study highlights fundamental differences between human and murine GBPs and underlines the need to study the functions of GBPs at cellular locations away from PVs.
authors.affiliation: Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, Mill Hill Laboratory, London, NW7 1AA, United Kingdom.
authors.forename: Ashleigh C
authors.initials: AC
authors.lastname: Johnston
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Piro
authors.affiliation: Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, Mill Hill Laboratory, London, NW7 1AA, United Kingdom.
authors.forename: Barbara
authors.initials: B
authors.lastname: Clough
authors.affiliation: Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, Mill Hill Laboratory, London, NW7 1AA, United Kingdom.
authors.forename: Malvin
authors.initials: M
authors.lastname: Siew
authors.affiliation: Max Planck Institute for Infection Biology, Charitéplatz 1, 10117, Berlin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Virreira Winter
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Jörn
authors.initials: J
authors.lastname: Coers
authors.affiliation: Host-Toxoplasma Interaction Laboratory, The Francis Crick Institute, Mill Hill Laboratory, London, NW7 1AA, United Kingdom.
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Frickel
mesh_terms: D000072283:A549 Cells; D002692:Chlamydia trachomatis / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology / Q000469:parasitology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D021381:Protein Transport; D012486:Salmonella typhimurium / Q000502:physiology; D014122:Toxoplasma / Q000502:physiology*; D014617:Vacuoles / Q000378:metabolism* / Q000469:parasitology
chemical_list: C490287:GBP1 protein, human; D019204:GTP-Binding Proteins