title: Regulatory interactions between IRG resistance GTPases in the cellular response to Toxoplasma gondii.
abstract: 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.
authors.affiliation: Department of Cell Genetics, Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: Julia P
authors.initials: JP
authors.lastname: Hunn
authors.forename: Stephanie
authors.initials: S
authors.lastname: Koenen-Waisman
authors.forename: Natasa
authors.initials: N
authors.lastname: Papic
authors.forename: Nina
authors.initials: N
authors.lastname: Schroeder
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Pawlowski
authors.forename: Rita
authors.initials: R
authors.lastname: Lange
authors.forename: Frank
authors.initials: F
authors.lastname: Kaiser
authors.forename: Jens
authors.initials: J
authors.lastname: Zerrahn
authors.forename: Sascha
authors.initials: S
authors.lastname: Martens
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Howard
mesh_terms: D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000382:microbiology / Q000502:physiology; D019204:GTP-Binding Proteins / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000502:physiology*; D007372:Interferons / Q000276:immunology*; D051379:Mice; D014122:Toxoplasma / Q000276:immunology* / Q000472:pathogenicity; D020798:Two-Hybrid System Techniques
chemical_list: D007372:Interferons; D019204:GTP-Binding Proteins
references.citation: J Immunol. 1998 Dec 15;161(12):6715-23
references.pmid: 9862701
references.citation: J Biol Chem. 1997 Apr 18;272(16):10639-45
references.pmid: 9099712
references.citation: J Immunol. 1998 Sep 1;161(5):2348-55
references.pmid: 9725230
references.citation: Mol Cell. 2004 Sep 10;15(5):727-39
references.pmid: 15350217
references.citation: J Biol Chem. 1996 Aug 23;271(34):20399-405
references.pmid: 8702776
references.citation: J Immunol. 2004 Aug 15;173(4):2594-606
references.pmid: 15294976
references.citation: J Histochem Cytochem. 1998 Dec;46(12):1411-22
references.pmid: 9815283
references.citation: Nature. 2006 Mar 2;440(7080):101-4
references.pmid: 16511497
references.citation: Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):751-5
references.pmid: 10639151
references.citation: Methods Enzymol. 2002;350:3-41
references.pmid: 12073320
references.citation: Genetics. 1996 Dec;144(4):1425-36
references.pmid: 8978031
references.citation: PLoS Pathog. 2005 Nov;1(3):e24
references.pmid: 16304607
references.citation: Infect Immun. 2005 Jun;73(6):3278-86
references.pmid: 15908352
references.citation: Mol Cell Biol. 1995 Oct;15(10):5820-9
references.pmid: 7565735
references.citation: Comb Chem High Throughput Screen. 2003 Jun;6(4):409-18
references.pmid: 12769685
references.citation: FEBS Lett. 1979 Nov 1;107(1):198-202
references.pmid: 499541
references.citation: Nature. 2004 Jan 15;427(6971):215-21
references.pmid: 14724630
references.citation: Science. 2001 Nov 9;294(5545):1299-304
references.pmid: 11701921
references.citation: Virology. 1973 Apr;52(2):456-67
references.pmid: 4705382
references.citation: Mol Cell Biol. 1988 Aug;8(8):3235-43
references.pmid: 3145408
references.citation: J Exp Med. 2001 Jul 16;194(2):181-8
references.pmid: 11457893
references.citation: J Immunol. 2005 Dec 15;175(12):8165-72
references.pmid: 16339555
references.citation: J Biol Chem. 2003 Aug 1;278(31):29336-43
references.pmid: 12732635
references.citation: Yeast. 1995 Apr 15;11(4):355-60
references.pmid: 7785336
references.citation: J Mol Biol. 2004 Nov 12;344(1):257-69
references.pmid: 15504415
references.citation: J Cell Sci. 2004 Apr 1;117(Pt 9):1747-56
references.pmid: 15075236
references.citation: Prog Biophys Mol Biol. 1996;66(1):1-41
references.pmid: 9107131
references.citation: Microbes Infect. 2007 Nov-Dec;9(14-15):1633-5
references.pmid: 18024123
references.citation: J Virol. 1993 Nov;67(11):6726-32
references.pmid: 8411374
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):14092-7
references.pmid: 16959883
references.citation: J Immunol. 2007 Nov 15;179(10):6963-72
references.pmid: 17982087
references.citation: EMBO J. 2006 Jun 21;25(12):2940-51
references.pmid: 16763562
references.citation: Trends Cell Biol. 2005 Jul;15(7):356-63
references.pmid: 15921909
references.citation: Cell Microbiol. 2007 Apr;9(4):841-8
references.pmid: 17346309
references.citation: J Immunol. 2004 Jan 15;172(2):1163-8
references.pmid: 14707092
references.citation: J Exp Med. 2006 Sep 4;203(9):2063-71
references.pmid: 16940170
references.citation: Cell Stem Cell. 2008 Jan 10;2(1):83-9
references.pmid: 18371424
references.citation: Annu Rev Cell Dev Biol. 2006;22:559-89
references.pmid: 16824009
references.citation: Genome Biol. 2005;6(11):R92
references.pmid: 16277747
references.citation: Mol Biol Cell. 1993 Jul;4(7):679-93
references.pmid: 7691276
references.citation: Proc Natl Acad Sci U S A. 1986 Feb;83(4):952-6
references.pmid: 3513168
references.citation: Nat Struct Biol. 2002 Feb;9(2):95-100
references.pmid: 11753431