Regulatory interactions between IRG resistance GTPases in the cellular response to Toxoplasma gondii

Julia P. Hunn, Stephanie Koenen-Waisman, Natasa Papic, Nina Schroeder, Nikolaus Pawlowski, Rita Lange, Frank Kaiser, Jens Zerrahn, Sascha Martens, Jonathan C. Howard

108 Citations (Scopus)


Members of the immunity-related GTPase (IRG) family are interferon-inducible resistance factors against a broad spectrum of intracellular pathogens including Toxoplasma gondii. The molecular mechanisms governing the function and regulation of the IRG resistance system are largely unknown. We find that IRG proteins function in a system of direct, nucleotide-dependent regulatory interactions between family members. After interferon induction but before infection, the three members of the GMS subfamily of IRG proteins, Irgm1, Irgm2 and Irgm3, which possess an atypical nucleotide-binding site, regulate the intracellular positioning of the conventional GKS subfamily members, Irga6 and Irgb6. Following infection, the normal accumulation of Irga6 protein at the parasitophorous vacuole membrane (PVM) is nucleotide dependent and also depends on the presence of all three GMS proteins. We present evidence that an essential role of the GMS proteins in this response is control of the nucleotide-bound state of the GKS proteins, preventing their GTP-dependent activation before infection. Accumulation of IRG proteins at the PVM has previously been shown to be associated with a block in pathogen replication: our results relate for the first time the enzymatic properties of IRG proteins to their role in pathogen resistance.

Original languageEnglish
JournalEMBO Journal
Issue number19
Pages (from-to)2495-2509
Number of pages15
Publication statusPublished - 08.10.2008

Research Areas and Centers

  • Research Area: Medical Genetics


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