Contacting domains segregate a lipid transporter from a solute transporter in the malarial host–parasite interface

Garten, Matthias; Beck, Josh R.; Roth, Robyn; Tenkova‐Heuser, Tatyana; Heuser, John E.; Istvan, Eva S.; Bleck, Christopher K. E.; Goldberg, Daniel E.; Zimmerberg, Joshua

doi:10.1038/s41467-020-17506-9

Cited by 20 publications

(22 citation statements)

References 52 publications

(81 reference statements)

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“…Compartmentation of the PV is suggested by fluorescence recovery after photobleaching (FRAP) analysis with a fluorescent reporter targeted to the PV lumen, which may result from regions of differential spacing between the PVM and PPM [ 18 , 86 ]. Indeed, while the PVM and PPM are kept in close proximity during intraerythrocytic development, recent observations reveal that the PV is arranged into 2 domains defined by distinct spacing constraints between these membranes yielding regions of extremely close apposition resembling membrane contact sites (approximately 9-nm PVM center to PPM center) and regions with expanded PV lumen (20- to 40-nm PVM center to PPM center) [ 87 ]. EXP2 and a soluble PV lumen reporter both localize to the latter regions, indicating that these are sites of protein export and solute transport.…”

Section: Small Molecule Transportmentioning

confidence: 99%

Transport mechanisms at the malaria parasite-host cell interface

Beck

2021

PLoS Pathog

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Obligate intracellular malaria parasites reside within a vacuolar compartment generated during invasion which is the principal interface between pathogen and host. To subvert their host cell and support their metabolism, these parasites coordinate a range of transport activities at this membrane interface that are critically important to parasite survival and virulence, including nutrient import, waste efflux, effector protein export, and uptake of host cell cytosol. Here, we review our current understanding of the transport mechanisms acting at the malaria parasite vacuole during the blood and liver-stages of development with a particular focus on recent advances in our understanding of effector protein translocation into the host cell by the Plasmodium Translocon of EXported proteins (PTEX) and small molecule transport by the PTEX membrane-spanning pore EXP2. Comparison to Toxoplasma gondii and other related apicomplexans is provided to highlight how similar and divergent mechanisms are employed to fulfill analogous transport activities.

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Section: Small Molecule Transportmentioning

confidence: 99%

Transport mechanisms at the malaria parasite-host cell interface

Beck

2021

PLoS Pathog

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“…The relative contribution of P113 is yet to be determined under each of these conditions, however, our data indicate that trapping cargo in PTEX (+WR) following reduction of P113 (+GlcN) significantly enhanced the formation of these blebs ( p < .0001) when compared to parasites in which cargo was trapped (+WR) but P113 expression was not altered (‐GlcN). Furthermore, in the absence of its membrane anchoring domain, P113 functioning appears to be compromised and the normal PVM morphology where the PVM and PPM are held in close apposition cannot be maintained (Garten et al, 2020). It is possible therefore that the role played by P113 in maintaining PVM architecture is linked to other processes at the PVM, however, further investigations are required to elucidate what precisely these functions may be.…”

Section: Discussionmentioning

confidence: 99%

The Plasmodium falciparum parasitophorous vacuole protein P113 interacts with the parasite protein export machinery and maintains normal vacuole architecture

Bullen

Sanders

Dans

et al. 2022

Molecular Microbiology

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Infection with Plasmodium falciparum parasites results in approximately 627,000 deaths from malaria annually. Key to the parasite’s success is their ability to invade and subsequently grow within human erythrocytes. Parasite proteins involved in parasite invasion and proliferation are therefore intrinsically of great interest, as targeting these proteins could provide novel means of therapeutic intervention. One such protein is P113 which has been reported to be both an invasion protein and an intracellular protein located within the parasitophorous vacuole (PV). The PV is delimited by a membrane (PVM) across which a plethora of parasite‐specific proteins are exported via the Plasmodium Translocon of Exported proteins (PTEX) into the erythrocyte to enact various immune evasion functions. To better understand the role of P113 we isolated its binding partners from in vitro cultures of P. falciparum. We detected interactions with the protein export machinery (PTEX and exported protein‐interacting complex) and a variety of proteins that either transit through the PV or reside on the parasite plasma membrane. Genetic knockdown or partial deletion of P113 did not significantly reduce parasite growth or protein export but did disrupt the morphology of the PVM, suggesting that P113 may play a role in maintaining normal PVM architecture.

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“…As HSP101 is expressed in Plasmodium liver stage forms (Matthews et al, 2013), its involvement in protein export into the hepatocyte appears likely, although it has not yet been proven. In Plasmodium trophozoites, areas of close contact between the PPM and the PVM can be observed, and domains of protein export can be observed on the PVM in these regions (Garten et al, 2020). It is not known whether the PPM of the Theileria schizont is similarly structured in patches with distinct functional regions, but the visualization of evenly distributed "knobs" on the PPM by high resolution scanning electron microscopy (SEM) could indicate the accumulation of specialized protein clusters on the parasite surface (Kuehni-Boghenbor et al, 2012).…”

Section: How Are Theileria Proteins Exported Across the Parasite Plasmentioning

confidence: 99%

Theileria’s Strategies and Effector Mechanisms for Host Cell Transformation: From Invasion to Immortalization

Woods

Perry

Brühlmann

et al. 2021

Front. Cell Dev. Biol.

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One of the first events that follows invasion of leukocytes by Theileria sporozoites is the destruction of the surrounding host cell membrane and the rapid association of the intracellular parasite with host microtubules. This is essential for the parasite to establish its niche within the cytoplasm of the invaded leukocyte and sets Theileria spp. apart from other members of the apicomplexan phylum such as Toxoplasma gondii and Plasmodium spp., which reside within the confines of a host-derived parasitophorous vacuole. After establishing infection, transforming Theileria species (T. annulata, T. parva) significantly rewire the signaling pathways of their bovine host cell, causing continual proliferation and resistance to ligand-induced apoptosis, and conferring invasive properties on the parasitized cell. Having transformed its target cell, Theileria hijacks the mitotic machinery to ensure its persistence in the cytoplasm of the dividing cell. Some of the parasite and bovine proteins involved in parasite-microtubule interactions have been fairly well characterized, and the schizont expresses at least two proteins on its membrane that contain conserved microtubule binding motifs. Theileria-encoded proteins have been shown to be translocated to the host cell cytoplasm and nucleus where they have the potential to directly modify signaling pathways and host gene expression. However, little is known about their mode of action, and even less about how these proteins are secreted by the parasite and trafficked to their target location. In this review we explore the strategies employed by Theileria to transform leukocytes, from sporozoite invasion until immortalization of the host cell has been established. We discuss the recent description of nuclear pore-like complexes that accumulate on membranes close to the schizont surface. Finally, we consider putative mechanisms of protein and nutrient exchange that might occur between the parasite and the host. We focus in particular on differences and similarities with recent discoveries in T. gondii and Plasmodium species.

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Contacting domains segregate a lipid transporter from a solute transporter in the malarial host–parasite interface

Cited by 20 publications

References 52 publications

Transport mechanisms at the malaria parasite-host cell interface

Transport mechanisms at the malaria parasite-host cell interface

The Plasmodium falciparum parasitophorous vacuole protein P113 interacts with the parasite protein export machinery and maintains normal vacuole architecture

Theileria’s Strategies and Effector Mechanisms for Host Cell Transformation: From Invasion to Immortalization

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