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• W2258255488 abstract "Members of the immunity-related (p47) GTPases (IRGs) are essential, interferon-inducible resistance factors active against a broad spectrum of important intracellular bacterial and protozoal pathogens including Toxoplasma gondii. Despite the strong, partially overlapping but non-redundant susceptibility phenotypes of mice genetically deficient for individual members of the family, little is known about molecular mechanisms of function and regulation of the IRG resistance system. This study demonstrates that IRG GTPases function in a system of direct, nucleotide-dependent regulatory interactions between family members. Spontaneous GTP-dependent homo-oligomerisation of the GKS subfamily member Irga6 leads to the activation of GTPase function in vitro. In vivo, accumulation of activated, GTP-bound GKS proteins at the parasitophorous vacuolar membrane is associated with the IFN-induced, cell autonomous destruction of avirulent Toxoplasma gondii. In contrast, direct GDP-dependent interactions of the unusual GMS subfamily members with the GKS proteins Irga6 and Irgb6 via the G-domains prevent premature activation of the resistance system in absence of infection. Lack of GMS GTPases results in spontaneous activation and aggregation of Irga6 and Irgb6 on endomembranes and hinders association with the parasitophorous vacuolar membrane upon infection with T. gondii. The three GMS GTPases are both necessary and sufficient to regulate Irga6 and Irgb6. No other interferon-inducible proteins are required for the regulation of the resting localisation of Irga6 and Irgb6 in the IFN-induced cell or for their infection-induced assembly on the membrane of the parasitophorous vacuole. Nucleotide binding is essential for the translocation from the resting localisation to the vacuole. Virulent Toxoplasma efficiently inhibited the recruitment of IRG proteins to the parasitophorous vacuole. These findings provide the first link between the enzymatic properties of IRG proteins as GTPases and their function in pathogen resistance. The IRG resistance GTPases are an ancient family that underwent extensive expansion and diversification as well as contraction in the euchordates - a feature characteristic for multigene families associated with pathogen resistance due to host-pathogen coevolution. Despite its essential role in resistance to vacuolar pathogens in mice, the IRG resistance system as such is not conserved in higher primates. While all other groups of mammals possess multiple divergent IRG genes, humans and higher primates contain a largely reduced set of typically three genes. All of these genes lack IFN-inducible elements in their putative promoters and are either significantly truncated, drastically damaged in the nucleotide binding domain or show testis-specific expression paralleling sexual maturity. Consequently, mice and humans must deploy their immune resources against vacuolar pathogens in radically different ways." @default.
• W2258255488 created "2016-06-24" @default.
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• W2258255488 date "2007-01-01" @default.
• W2258255488 modified "2023-09-27" @default.
• W2258255488 title "Evolution and Cellular Resistance Mechanisms of the Immunity-Related GTPases" @default.
• W2258255488 hasPublicationYear "2007" @default.
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