The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage

Bekpen, Cemalettin; Hunn, Julia P.; Rohde, Christoph; Parvanova, Iana; Guethlein, Libby; Dunn, Diane M.; Glowalla, Eva; Leptin, Maria; Howard, Jonathan

doi:10.1186/gb-2005-6-11-r92

Cited by 267 publications

(245 citation statements)

References 70 publications

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“…Indeed, sequencing of the genomic region upstream of Irgb10 reveals an A B6 -to-G C3H transition that mutates one of two IFN-stimulated response elements (GCTTTCAGTTTC, where the site of the polymorphism is underlined) that lie within 100 bp of the putative transcription initiation site (19). The effect of this polymorphism on expression is unclear because this promoter element will accept either an A or a G at this central nucleotide position and still be bound by the Irf1 and Irf2 transcription factors (22).…”

Section: Discussionmentioning

confidence: 99%

“…Members of this gene family are strongly induced by IFN-␥, localize to pathogencontaining vacuoles, and play critical roles in resistance to a variety of intracellular pathogens in mice (16)(17)(18). One of the p47 GTPases in our critical genetic interval is Igtp; the other is annotated as a gene model in the current genome build but has recently been designated Irgb10 (19). Although Irgb10 had been thought to be truncated, we successfully reverse-transcribed what appears to be full-length Irgb10 coding sequence from RNA isolated from the spleens of mice infected for 4 h with C. trachomatis L2.…”

Section: Ctrq-3 Contains Two Members Of the P47 Family Of Gtpasesmentioning

confidence: 99%

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The p47 GTPases Igtp and Irgb10 map to the Chlamydia trachomatis susceptibility locus Ctrq-3 and mediate cellular resistance in mice

Bernstein-Hanley

Coers²,

Balsara³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Infections caused by the bacteria Chlamydia trachomatis contribute to diverse pathologies in a variety of human populations. We previously used a systemic model of C. trachomatis infection in mice to map three quantitative trait loci that influence in vivo susceptibility differences between the C57BL͞6J and C3H͞HeJ inbred strains of mouse. One of these quantitative trait loci, Ctrq-3, influences an IFN-␥-dependent susceptibility difference in primary embryonic fibroblasts isolated from these strains. Here we use fine structure mapping in congenic fibroblasts carrying DNA from the susceptible parent to localize the effect of Ctrq-3 to a 1.2-megabase interval of genomic DNA that contains Irgb10 and Igtp, two members of the IFN-␥-inducible p47 family of GTPases. This class of proteins has been widely implicated in resistance to intracellular pathogens in mice. We analyzed expression of Irgb10 and Igtp in parental and congenic embryonic fibroblasts treated with IFN-␥ and found that relatively resistant fibroblasts express more Irgb10 than relatively susceptible fibroblasts. However, we also found that abolishing the expression of either Irgb10 or Igtp increases susceptibility of embryonic fibroblasts to C. trachomatis. Thus, we conclude that, although a difference in Irgb10 expression is likely responsible for the effect of Ctrq-3 on susceptibility to C. trachomatis, both genes play a role in intracellular resistance to C. trachomatis.genetic ͉ infection ͉ mouse ͉ immunity ͉ interferon

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Section: Discussionmentioning

confidence: 99%

Section: Ctrq-3 Contains Two Members Of the P47 Family Of Gtpasesmentioning

confidence: 99%

The p47 GTPases Igtp and Irgb10 map to the Chlamydia trachomatis susceptibility locus Ctrq-3 and mediate cellular resistance in mice

Bernstein-Hanley

Coers²,

Balsara³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…IRG proteins represent a complex family of polymorphic interferon gamma (IFNγ)‐inducible GTPases (Boehm et al ., 1998; Martens and Howard, 2006). About 20 IRG genes are encoded within the genome of C57BL/6 mice, located in two adjacent clusters on chromosome 11 and one cluster on chromosome 18 (Bekpen et al ., 2005). Four of these genes are transcribed as adjacent pairs, resulting in expression of proteins carrying two IRG domains, the so‐called tandem IRG proteins (Lilue et al ., 2013).…”

Section: Introductionmentioning

confidence: 99%

TheToxoplasma gondiirhoptry protein ROP18 is an Irga6‐specific kinase and regulated by the dense granule protein GRA7

Hermanns

Müller

Könen‐Waisman

et al. 2015

Cellular Microbiology

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SummaryIn mice, avirulent strains (e.g. types II and III) of the protozoan parasite Toxoplasma gondii are restricted by the immunity‐related GTPase (IRG) resistance system. Loading of IRG proteins onto the parasitophorous vacuolar membrane (PVM) is required for vacuolar rupture resulting in parasite clearance. In virulent strain (e.g. type I) infections, polymorphic effector proteins ROP5 and ROP18 cooperate to phosphorylate and thereby inactivate mouse IRG proteins to preserve PVM integrity. In this study, we confirmed the dense granule protein GRA7 as an additional component of the ROP5/ROP18 kinase complex and identified GRA7 association with the PVM by direct binding to ROP5. The absence of GRA7 results in reduced phosphorylation of Irga6 correlated with increased vacuolar IRG protein amounts and attenuated virulence. Earlier work identified additional IRG proteins as targets of T. gondii ROP18 kinase. We show that the only specific target of ROP18 among IRG proteins is in fact Irga6. Similarly, we demonstrate that GRA7 is strictly an Irga6‐specific virulence effector. This identifies T. gondii GRA7 as a regulator for ROP18‐specific inactivation of Irga6. The structural diversity of the IRG proteins implies that certain family members constitute additional specific targets for other yet unknown T. gondii virulence effectors.

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“…Irga6 possesses a Ras-like GTP-binding domain slung between two helical modules of unknown function. The N terminus carries a myristoylation signal (14) that is active in vivo (15). The nonmyristoylated protein purified from Escherichia coli has affinities in the micromolar range for GDP (ϳ1 M) and for GTP (ϳ15 M) and a low basal turnover rate from GTP to GDP of less than 0.1/min (16).…”

mentioning

confidence: 99%

Inactive and Active States of the Interferon-inducible Resistance GTPase, Irga6, in Vivo

Papic

Hunn

Pawlowski

et al. 2008

Journal of Biological Chemistry

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Irga6, a myristoylated, interferon-inducible member of the immunity-related GTPase family, contributes to disease resistance against Toxoplasma gondii in mice. Accumulation of Irga6 on the T. gondii parasitophorous vacuole membrane is associated with vesiculation and ultimately disruption of the vacuolar membrane in a process that requires an intact GTP-binding domain. The role of the GTP-binding domain of Irga6 in pathogen resistance is, however, unclear. We provide evidence that Irga6 in interferon-induced, uninfected cells is predominantly in a GDP-bound state that is maintained by other interferoninduced proteins. However, Irga6 that accumulates on the parasitophorous vacuole membrane after Toxoplasma infection is in the GTP-bound form. We demonstrate that a monoclonal antibody, 10D7, specifically detects GTP-bound Irga6, and we show that the formation of the 10D7 epitope follows from a GTP-dependent conformational transition of the N terminus of Irga6, anticipating an important role of the myristoyl group on Irga6 function in vivo.

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The interferon-inducible p47 (IRG) GTPases in vertebrates: loss of the cell autonomous resistance mechanism in the human lineage

Abstract: Background: Members of the p47 (immunity-related GTPases (IRG) family) GTPases are essential, interferon-inducible resistance factors in mice that are active against a broad spectrum of important intracellular pathogens. Surprisingly, there are no reports of p47 function in humans.

Cited by 267 publications

References 70 publications

The p47 GTPases Igtp and Irgb10 map to the Chlamydia trachomatis susceptibility locus Ctrq-3 and mediate cellular resistance in mice

The p47 GTPases Igtp and Irgb10 map to the Chlamydia trachomatis susceptibility locus Ctrq-3 and mediate cellular resistance in mice

TheToxoplasma gondiirhoptry protein ROP18 is an Irga6‐specific kinase and regulated by the dense granule protein GRA7

Inactive and Active States of the Interferon-inducible Resistance GTPase, Irga6, in Vivo

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