The<i>Toxoplasma gondii</i>rhoptry protein ROP18 is an Irga6‐specific kinase and regulated by the dense granule protein GRA7

Hermanns, Thomas; Müller, Urs Benedikt; Könen‐Waisman, Stephanie; Howard, Jonathan C.; Steinfeldt, Tobias

doi:10.1111/cmi.12499

Cited by 70 publications

(82 citation statements)

References 50 publications

(127 reference statements)

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“…These in vitro studies suggest that in vivo GRA7 acts to increase turnover of IRGs, thus displacing them from the PV membrane and making monomeric substrates available for phosphorylation by ROP18. Other studies confirm that GRA7 is needed for maximum activity of ROP18 against the substrate Irga6 in infected cells (43), perhaps reflecting the enhanced turnover described above together with the close physical proximity of ROP18 and GRA7, which form a large complex in the cell (5). ROP5 and ROP18 also contribute to the ability of virulent strains of T. gondii to avoid recruitment of GBPs to the PV membrane; these appear to act downstream of IRGs in the control of intracellular…”

Section: Targeting Of Host Innate Immunitymentioning

confidence: 85%

Genetic Mapping of Pathogenesis Determinants inToxoplasma gondii

Behnke

Dubey

Sibley

2016

Annu. Rev. Microbiol.

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Toxoplasma gondii is a widespread parasite of warm-blooded vertebrates that also causes opportunistic infections in humans. Rodents are a natural host for asexually replicating forms, whereas cats serve as the definitive host for sexual development. The laboratory mouse provides a model to study pathogenesis. Strains of T. gondii are globally diverse, with more than 16 distinct haplogroups clustered into 6 major clades. Forward genetic analysis of genetic crosses between different lineages has been used to define the molecular basis of acute virulence in the mouse. These studies have identified a family of secretory serine/threonine rhoptry kinases that target innate immune pathways to protect intracellular parasites from destruction. Rhoptry kinases target immunity-related GTPases, a family of immune effectors that is expanded in rodents. Similar forward genetic studies may be useful to define the basis of pathogenesis in other hosts, including humans, where infections of different strains present with variable clinical severity.

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Section: Targeting Of Host Innate Immunitymentioning

confidence: 85%

Genetic Mapping of Pathogenesis Determinants inToxoplasma gondii

Behnke

Dubey

Sibley

2016

Annu. Rev. Microbiol.

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“…The localization of IRGs to the PVM can be inhibited mainly through the ROP5/17/18 complex . In addition, GRA7 can bind to oligomers of Irga6, acting synergistically with ROP18 to control the localization of IRGs onto the PVM, although deletion of GRA7 has not or slightly increased the IRGs’ recruitment . We wondered whether GRA12 and ROP18 act in a complex to target IRGs, likewise GRA7.…”

Section: Discussionmentioning

confidence: 99%

“…PVM‐localized effector proteins are secreted from two major organelles: the dense granule (GRA) and the rhoptry (ROP), which subvert the host cellular functions by interacting with the PVM to protect T. gondii against host deleterious defense and clearance mechanisms, or crossing the PVM and translocating to nucleus to regulate the gene expression . The kinase ROP18 and pseudokinase ROP5 function together to inactivate host immunity‐related GTPase (IRGs) by phosphorylation, thereby preventing degradation of the PV and promoting parasite survival in mice . GRA18 traffics across the PVM to reach the cytoplasm of infected host cells where it forms complexes with host components of the β‐catenin destruction complex to regulate the host gene expression in a β‐catenin‐dependent fashion .…”

Section: Introductionmentioning

confidence: 99%

Novel roles of dense granule protein 12 (GRA12) inToxoplasma gondiiinfection

et al. 2020

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are contributed equally to this work. AbstractDense granule protein 12 (GRA12) is implicated in a range of processes related to the establishment of Toxoplasma gondii infection, such as the formation of the intravacuolar network (IVN) within the parasitophorous vacuole (PV). This protein is also thought to be important for T. gondii-host interaction, pathogenesis, and immune evasion, but their exact roles remain unknown. In this study, the contributions of GRA12 to the molecular pathogenesis of T. gondii infection were examined in vitro and in vivo. Deletion of GRA12 in type I RH and type II Pru T. gondii strains did not affect the parasite growth and replication in vitro, however, it caused a significant reduction in the parasite virulence and tissue cyst burden in vivo. T. gondii Δgra12 mutants were more vulnerable to be eliminated by host immunity, without the accumulation of immunity-related GTPase a6 (Irga6) onto the PV membrane.The ultrastructure of IVN in Δgra12 mutants appeared normal, suggesting that GRA12 is not required for biogenesis of the IVN. Combined deletion of GRA12 and ROP18 induced more severe attenuation of virulence compared to single Δgra12 or Δrop18 mutant strains. These data suggest a functional association between GRA12 and ROP18 that is revealed by the severe attenuation of virulence in a double mutant relative to the single individual mutations. Future studies are needed to define the molecular basis of this putative association. Collectively these findings indicate that although GRA12 is not essential for the parasite growth and replication in vitro, it contributes to the virulence and growth of T. gondii in mice. K E Y W O R D Sdense granule protein 12, immunity-related GTPases, intravacuolar network, rhoptry protein 18, Toxoplasma gondii, virulence 3166 | WANG et Al. SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section. How to cite this article: Wang J-L, Bai M-J, Elsheikha HM, et al. Novel roles of dense granule protein 12 (GRA12) in Toxoplasma gondii infection.

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“…GRA7 contributes to inhibition of vacuolar IRG protein accumulation at the PVM and is Irga6 specific. It has been demonstrated that T. gondii GRA7 as a regulator of ROP18-specific inactivation of Irga6 in vivo (49). The structural diversity of the IRG proteins implies that certain family members constitute additional specific targets for other, as-yet-unknown, T. gondii virulence effectors.…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma gondii GRA7-Induced TRAF6 Activation Contributes to Host Protective Immunity

et al. 2016

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The intracellular parasite Toxoplasma gondii has unique dense granule antigens (GRAs) that are crucial for host infection. Emerging evidence suggests that GRA7 of T. gondii is a promising serodiagnostic marker and an effective toxoplasmosis vaccine candidate; however, little is known about the intracellular regulatory mechanisms involved in the GRA7-induced host responses. Here we show that GRA7-induced MyD88 signaling through the activation of TRAF6 and production of reactive oxygen species (ROS) is required for the induction of NF-B-mediated proinflammatory responses by macrophages. GRA7 stimulation resulted in the rapid activation of mitogen-activated protein kinases and an early burst of ROS in macrophages in a MyD88-dependent manner. GRA7 induced a physical association between GRA7 and TRAF6 via MyD88. Remarkably, the C terminus of GRA7 (GRA7-V) was sufficient for interaction with and ubiquitination of the RING domain of TRAF6, which is capable of inflammatory cytokine production. Interestingly, the generation of ROS and TRAF6 activation are mutually dependent on GRA7/MyD88-mediated signaling in macrophages. Furthermore, mice immunized with GRA7-V showed markedly increased Th1 immune responses and protective efficacy against T. gondii infection. Collectively, these results provide novel insight into the crucial role of GRA7-TRAF6 signaling in innate immune responses.

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

Cited by 70 publications

References 50 publications

Genetic Mapping of Pathogenesis Determinants inToxoplasma gondii

Genetic Mapping of Pathogenesis Determinants inToxoplasma gondii

Novel roles of dense granule protein 12 (GRA12) inToxoplasma gondiiinfection

Toxoplasma gondii GRA7-Induced TRAF6 Activation Contributes to Host Protective Immunity

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