title: Phosphorylation of immunity-related GTPases by a Toxoplasma gondii-secreted kinase promotes macrophage survival and virulence.
abstract: Macrophages are specialized to detect and destroy intracellular microbes and yet a number of pathogens have evolved to exploit this hostile niche. Here we demonstrate that the obligate intracellular parasite Toxoplasma gondii disarms macrophage innate clearance mechanisms by secreting a serine threonine kinase called ROP18, which binds to and phosphorylates immunity-related GTPases (IRGs). Substrate profiling of ROP18 revealed a preference for a conserved motif within switch region I of the GTPase domain, a modification predicted to disrupt IRG function. Consistent with this, expression of ROP18 was both necessary and sufficient to block recruitment of Irgb6, which was in turn required for parasite destruction. ROP18 phosphorylation of IRGs prevented clearance within inflammatory monocytes and IFN-γ-activated macrophages, conferring parasite survival in vivo and promoting virulence. IRGs are implicated in clearance of a variety of intracellular pathogens, suggesting that other virulence factors may similarly thwart this innate cellular defense mechanism.
authors.affiliation: Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63130, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Fentress
authors.forename: Michael S
authors.initials: MS
authors.lastname: Behnke
authors.forename: Ildiko R
authors.initials: IR
authors.lastname: Dunay
authors.forename: Mona
authors.initials: M
authors.lastname: Mashayekhi
authors.forename: Leah M
authors.initials: LM
authors.lastname: Rommereim
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Fox
authors.forename: David J
authors.initials: DJ
authors.lastname: Bzik
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Taylor
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.forename: Cheryl F
authors.initials: CF
authors.lastname: Lichti
authors.forename: R Reid
authors.initials: RR
authors.lastname: Townsend
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.forename: Raymond
authors.initials: R
authors.lastname: Hui
authors.forename: Wandy L
authors.initials: WL
authors.lastname: Beatty
authors.forename: L David
authors.initials: LD
authors.lastname: Sibley
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D019204:GTP-Binding Proteins / Q000276:immunology / Q000502:physiology*; D007113:Immunity, Innate; D008264:Macrophages / Q000276:immunology / Q000469:parasitology* / Q000473:pathology; D051379:Mice; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000502:physiology*; D015800:Protozoan Proteins; D014122:Toxoplasma / Q000502:physiology*; D014774:Virulence
chemical_list: D015800:Protozoan Proteins; D017346:Protein Serine-Threonine Kinases; C556793:ROP18 protein, Toxoplasma gondii; D019204:GTP-Binding Proteins