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Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p47-resistance GTPases.

ABSTRACT: The p47 GTPases are essential for interferon-gamma-induced cell-autonomous immunity against the protozoan parasite, Toxoplasma gondii, in mice, but the mechanism of resistance is poorly understood. We show that the p47 GTPases, including IIGP1, accumulate at vacuoles containing T. gondii. The accumulation is GTP-dependent and requires live parasites. Vacuolar IIGP1 accumulations undergo a maturation-like process accompanied by vesiculation of the parasitophorous vacuole membrane. This culminates in disruption of the parasitophorous vacuole and finally of the parasite itself. Over-expression of IIGP1 leads to accelerated vacuolar disruption whereas a dominant negative form of IIGP1 interferes with interferon-gamma-mediated killing of intracellular parasites. Targeted deletion of the IIGP1 gene results in partial loss of the IFN-gamma-mediated T. gondii growth restriction in mouse astrocytes.

SUBMITTER: Martens S

PROVIDER: S-EPMC1287907 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p47-resistance GTPases.

Martens Sascha S Parvanova Iana I Zerrahn Jens J Griffiths Gareth G Schell Gudrun G Reichmann Gaby G Howard Jonathan C JC

PLoS pathogens 20051118 3

The p47 GTPases are essential for interferon-gamma-induced cell-autonomous immunity against the protozoan parasite, Toxoplasma gondii, in mice, but the mechanism of resistance is poorly understood. We show that the p47 GTPases, including IIGP1, accumulate at vacuoles containing T. gondii. The accumulation is GTP-dependent and requires live parasites. Vacuolar IIGP1 accumulations undergo a maturation-like process accompanied by vesiculation of the parasitophorous vacuole membrane. This culminates ...[more]

PMID: 16304607

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Project description:The obligate intracellular protozoan pathogen Toxoplasma gondii infects a wide range of vertebrate hosts and frequently causes zoonotic infections in humans. Whereas infected immunocompetent individuals typically remain asymptomatic, toxoplasmosis in immunocompromised individuals can manifest as a severe, potentially lethal disease, and congenital Toxoplasma infections are associated with adverse pregnancy outcomes. The protective immune response of healthy individuals involves the production of lymphocyte-derived cytokines such as interferon gamma (IFN-γ), which elicits cell-autonomous immunity in host cells. IFN-γ-inducible antiparasitic defense programs comprise nutritional immunity, the production of noxious gases, and the ubiquitylation of the Toxoplasma-containing parasitophorous vacuole (PV). PV ubiquitylation prompts the recruitment of host defense proteins to the PV and the consequential execution of antimicrobial effector programs, which reduce parasitic burden. However, the ubiquitin E3 ligase orchestrating these events has remained unknown. Here, we demonstrate that the IFN-γ-inducible E3 ligase RNF213 translocates to Toxoplasma PVs and facilitates PV ubiquitylation in human cells. Toxoplasma PVs become decorated with linear and K63-linked ubiquitin and recruit ubiquitin adaptor proteins in a process that is RNF213 dependent but independent of the linear ubiquitin chain assembly complex (LUBAC). IFN-γ priming fails to restrict Toxoplasma growth in cells lacking RNF213 expression, thus identifying RNF213 as a potent executioner of ubiquitylation-driven antiparasitic host defense. IMPORTANCE Globally, approximately one out of three people become infected with the obligate intracellular parasite Toxoplasma. These infections are typically asymptomatic but can cause severe disease and mortality in immunocompromised individuals. Infections can also be passed on from mother to fetus during pregnancy, potentially causing miscarriage or stillbirth. Therefore, toxoplasmosis constitutes a substantial public health burden. A better understanding of mechanisms by which healthy individuals control Toxoplasma infections could provide roadmaps toward novel therapies for vulnerable groups. Our work reveals a fundamental mechanism controlling intracellular Toxoplasma infections. Cytokines produced during Toxoplasma infections instruct human cells to produce the enzyme RNF213. We find that RNF213 labels intracellular vacuoles containing Toxoplasma with the small protein ubiquitin, which functions as an "eat-me" signal, attracting antimicrobial defense programs to fight off infection. Our work therefore identified a novel antiparasitic protein orchestrating a central aspect of the human immune response to Toxoplasma.

Dataset Information

Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p47-resistance GTPases.

Publications

Disruption of Toxoplasma gondii parasitophorous vacuoles by the mouse p47-resistance GTPases.

Similar Datasets

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