TY - JOUR
T1 - Regulatory interactions between IRG resistance GTPases in the cellular response to Toxoplasma gondii
AU - Hunn, Julia P.
AU - Koenen-Waisman, Stephanie
AU - Papic, Natasa
AU - Schroeder, Nina
AU - Pawlowski, Nikolaus
AU - Lange, Rita
AU - Kaiser, Frank
AU - Zerrahn, Jens
AU - Martens, Sascha
AU - Howard, Jonathan C.
PY - 2008/10/8
Y1 - 2008/10/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=53549109432&partnerID=8YFLogxK
U2 - 10.1038/emboj.2008.176
DO - 10.1038/emboj.2008.176
M3 - Journal articles
C2 - 18772884
AN - SCOPUS:53549109432
SN - 0261-4189
VL - 27
SP - 2495
EP - 2509
JO - EMBO Journal
JF - EMBO Journal
IS - 19
ER -
