title: IRG and GBP host resistance factors target aberrant, "non-self" vacuoles characterized by the missing of "self" IRGM proteins.
abstract: Interferon-inducible GTPases of the Immunity Related GTPase (IRG) and Guanylate Binding Protein (GBP) families provide resistance to intracellular pathogenic microbes. IRGs and GBPs stably associate with pathogen-containing vacuoles (PVs) and elicit immune pathways directed at the targeted vacuoles. Targeting of Interferon-inducible GTPases to PVs requires the formation of higher-order protein oligomers, a process negatively regulated by a subclass of IRG proteins called IRGMs. We found that the paralogous IRGM proteins Irgm1 and Irgm3 fail to robustly associate with "non-self" PVs containing either the bacterial pathogen Chlamydia trachomatis or the protozoan pathogen Toxoplasma gondii. Instead, Irgm1 and Irgm3 reside on "self" organelles including lipid droplets (LDs). Whereas IRGM-positive LDs are guarded against the stable association with other IRGs and GBPs, we demonstrate that IRGM-stripped LDs become high affinity binding substrates for IRG and GBP proteins. These data reveal that intracellular immune recognition of organelle-like structures by IRG and GBP proteins is partly dictated by the missing of "self" IRGM proteins from these structures.
authors.affiliation: Departments of Molecular Genetics and Microbiology, and Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Haldar
authors.forename: Hector A
authors.initials: HA
authors.lastname: Saka
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Piro
authors.forename: Joe Dan
authors.initials: JD
authors.lastname: Dunn
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Henry
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Taylor
authors.forename: Eva M
authors.initials: EM
authors.lastname: Frickel
authors.forename: Raphael H
authors.initials: RH
authors.lastname: Valdivia
authors.forename: Jörn
authors.initials: J
authors.lastname: Coers
mesh_terms: D000818:Animals; D002460:Cell Line; D002690:Chlamydia Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002692:Chlamydia trachomatis / Q000276:immunology* / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate; D051379:Mice; D018345:Mice, Knockout; D014122:Toxoplasma / Q000276:immunology* / Q000378:metabolism; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014617:Vacuoles / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology / Q000469:parasitology
chemical_list: C096000:Ifi1 protein, mouse; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C491070:Iigp1 protein, mouse