Vacuolar and plasma membrane stripping and autophagic elimination of <i>Toxoplasma gondii</i> in primed effector macrophages

Ling, Yun; Shaw, Michael H.; Ayala, Carol A.; Coppens, Isabelle; Taylor, Gregory A.; Ferguson, David J. P.; Yap, George

doi:10.1084/jem.20061318

Cited by 324 publications

(289 citation statements)

References 30 publications

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“…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

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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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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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“…Concomitant with Toxoplasma penetrating into its host cell, it forms its PV, while avoiding the endolysosomal pathway, since that route would result in autophagy-mediated degradation of the PV and parasite (41)(42)(43). Parasite avoidance of the phagolysosome is inhibited by treatment of cells with tyrosine kinase inhibitors, and the epidermal growth factor (EGF) receptor, which is a receptor tyrosine kinase, was identified as at least one target of these inhibitors (44).…”

Section: The Host Plasma Membrane As a Key Target For Toxoplasma To Rmentioning

confidence: 99%

Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond

Blader

Koshy

2014

Eukaryot Cell

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b Intracellular pathogens can replicate efficiently only after they manipulate and modify their host cells to create an environment conducive to replication. While diverse cellular pathways are targeted by different pathogens, metabolism, membrane and cytoskeletal architecture formation, and cell death are the three primary cellular processes that are modified by infections. Toxoplasma gondii is an obligate intracellular protozoan that infects ϳ30% of the world's population and causes severe and lifethreatening disease in developing fetuses, in immune-comprised patients, and in certain otherwise healthy individuals who are primarily found in South America. The high prevalence of Toxoplasma in humans is in large part a result of its ability to modulate these three host cell processes. Here, we highlight recent work defining the mechanisms by which Toxoplasma interacts with these processes. In addition, we hypothesize why some processes are modified not only in the infected host cell but also in neighboring uninfected cells.T oxoplasma gondii is a protozoan, obligate intracellular parasite that is considered one of the world's most successful pathogens (1). Multiple factors contribute to this success, including a complex life cycle in which the parasite can be transmitted by both vertical and horizontal means, efficient propagation within both its primary (felines) and intermediate hosts, extensive mechanisms to evade and disarm host immunity, an ability to form chronic lifelong infections in intermediate hosts, and a wide host tropism in which the parasite can infect most nucleated cells of warm-blooded animals (2). Central to most of these factors is that Toxoplasma has developed the means to replicate efficiently within the hostile intracellular environment of its host cell. In this review, we highlight recent data that have shed light on how parasite growth is achieved by the parasite interacting with its host cell to manipulate host signaling cascades, transcription, cell survival pathways, and membrane transport. In addition, we discuss how parasites interact with neighboring host cells and propose how this may contribute to establishing a permissive microenvironment to improve its overall success. In particular, we focus on those processes that are essential for the growth of all parasite strains and we refer readers to recent reviews that highlight how polymorphic parasite molecules contribute to Toxoplasma virulence (3-5). NUTRIENT ACQUISITIONAs an obligate intracellular parasite that resides within a nonfusogenic vacuole, Toxoplasma must satisfy its nutritional needs by scavenging essential nutrients from its host cell. These nutrients include carbon sources (glucose and glutamine) to fuel its energy demands, specific amino acids, lipids, and other nutrients. Below, we discuss each of these and highlight pathways and processes that are unique to the parasite that could serve as novel drug targets (Fig. 1). GLUCOSE AND GLUTAMINE POWER THE PARASITEToxoplasma expresses a full complement of glycolytic and tr...

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“…IRG 3 proteins are 47-kDa, interferon-inducible GTPases intimately involved in disease resistance against intracellular parasites in mice (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Some biochemical parameters and the crystal structure of one member of the family, Irga6 (formerly IIGP1), have been determined (13).…”

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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Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages

Cited by 324 publications

References 30 publications

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

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

Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond

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

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