Disruption of Toxoplasma gondii Parasitophorous Vacuoles by the Mouse p47-Resistance GTPases

Martens, Sascha; Parvanova, Iana; Zerrahn, Jens; Griffiths, Gareth; Schell, Gudrun; Reichmann, Gaby; Howard, Jonathan C.

doi:10.1371/journal.ppat.0010024

Cited by 329 publications

(516 citation statements)

References 61 publications

Supporting

Mentioning

486

Contrasting

Unclassified

Order By: Relevance

“…Results from studies involving other p47 GTPases suggest that this class of proteins may influence trafficking events around the parasitophorous vacuole in which many intracellular pathogens reside (24,25). Indeed, our own preliminary studies involving epitope-tagged alleles of Irgb10 suggest that this protein (but not Igtp) localizes to the inclusion membrane itself (data not shown).…”

Section: Discussionmentioning

confidence: 89%

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.

View full text Add to dashboard Cite

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

show abstract

Section: Discussionmentioning

confidence: 89%

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.

View full text Add to dashboard Cite

show abstract

“…Based upon a unique substitution within the first nucleotide binding motif (GX 4 G K / M S), IRG proteins can be classified into two subfamilies. Activated GTP‐bound effector IRG proteins (the G K S group) accumulate in high densities at the parasitophorous vacuolar membrane (PVM) of avirulent T. gondii type II strains early after invasion, leading to PVM rupture and parasite clearance (Martens et al ., 2005; Ling et al ., 2006; Zhao et al ., 2009b). The loading is cooperative and hierarchical, with two family members serving as pioneers for members loading later (Khaminets et al ., 2010).…”

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

View full text Add to dashboard Cite

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.

show abstract

“…Critical mediators of host-directed attacks on PVs are two families of IFNγ-inducible GTPases: immunityrelated GTPases (IRGs) and guanylate binding proteins (GBPs) (2). Members of both GTPase families play roles in host-mediated lysis of PVs, a process resulting in the release of microbes into the host cell cytoplasm, subsequent killing of PV-expelled microbes, and host cell death (3)(4)(5)(6)(7)(8). Additionally, GBPs help deliver cytosolic subunits of the antimicrobial NADPH oxidase NOX2 for assembly on phagosomal membranes, orchestrate the capture of PV-resident microbes inside degradative autophagolysosomes, and promote the activation of canonical and noncanonical inflammasome pathways (5,(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins

Haldar

Foltz

Finethy

et al. 2015

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

151

237

View full text Add to dashboard Cite

Many microbes create and maintain pathogen-containing vacuoles (PVs) as an intracellular niche permissive for microbial growth and survival. The destruction of PVs by IFNγ-inducible guanylate binding protein (GBP) and immunity-related GTPase (IRG) host proteins is central to a successful immune response directed against numerous PV-resident pathogens. However, the mechanism by which IRGs and GBPs cooperatively detect and destroy PVs is unclear. We find that host cell priming with IFNγ prompts IRG-dependent association of Toxoplasma- and Chlamydia-containing vacuoles with ubiquitin through regulated translocation of the E3 ubiquitin ligase tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6). This initial ubiquitin labeling elicits p62-mediated escort and deposition of GBPs to PVs, thereby conferring cell-autonomous immunity. Hypervirulent strains of Toxoplasma gondii evade this process via specific rhoptry protein kinases that inhibit IRG function, resulting in blockage of downstream PV ubiquitination and GBP delivery. Our results define a ubiquitin-centered mechanism by which host cells deliver GBPs to PVs and explain how hypervirulent parasites evade GBP-mediated immunity.

show abstract

Disruption of Toxoplasma gondii Parasitophorous Vacuoles by the Mouse p47-Resistance GTPases

Cited by 329 publications

References 61 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

Ubiquitin systems mark pathogen-containing vacuoles as targets for host defense by guanylate binding proteins

Contact Info

Product

Resources

About