title: Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins.
abstract: Many microbes create and maintain pathogen-containing vacuoles (PVs) as an intracellular niche permissive for microbial growth and survival. The destruction of PVs by IFNγ-inducible guanylate binding protein (GBP) and immunity-related GTPase (IRG) host proteins is central to a successful immune response directed against numerous PV-resident pathogens. However, the mechanism by which IRGs and GBPs cooperatively detect and destroy PVs is unclear. We find that host cell priming with IFNγ prompts IRG-dependent association of Toxoplasma- and Chlamydia-containing vacuoles with ubiquitin through regulated translocation of the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6). This initial ubiquitin labeling elicits p62-mediated escort and deposition of GBPs to PVs, thereby conferring cell-autonomous immunity. Hypervirulent strains of Toxoplasma gondii evade this process via specific rhoptry protein kinases that inhibit IRG function, resulting in blockage of downstream PV ubiquitination and GBP delivery. Our results define a ubiquitin-centered mechanism by which host cells deliver GBPs to PVs and explain how hypervirulent parasites evade GBP-mediated immunity.
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC 27710;
authors.forename: Arun K
authors.initials: AK
authors.lastname: Haldar
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom;
authors.forename: Clémence
authors.initials: C
authors.lastname: Foltz
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC 27710;
authors.forename: Ryan
authors.initials: R
authors.lastname: Finethy
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC 27710;
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Piro
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC 27710;
authors.forename: Eric M
authors.initials: EM
authors.lastname: Feeley
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC 27710;
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Pilla-Moffett
authors.affiliation: Department of Biochemistry, School of Medicine Niigata University, Niigata-shi, 951-8510, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Komatsu
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, United Kingdom;
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Frickel
authors.affiliation: Departments of Molecular Genetics and Microbiology and Immunology, Duke University Medical Center, Durham, NC 27710; jorn.coers@duke.edu.
authors.forename: Jörn
authors.initials: J
authors.lastname: Coers
mesh_terms: D000818:Animals; D002690:Chlamydia Infections / Q000276:immunology*; D002692:Chlamydia trachomatis / Q000276:immunology*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology*; D057131:Immune Evasion; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology; D014617:Vacuoles / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology
chemical_list: D048029:TNF Receptor-Associated Factor 6; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D019204:GTP-Binding Proteins
keywords: Chlamydia; GBPs; Toxoplasma; immunity-related GTPase; interferon