Host cell remodeling by pathogens: the exomembrane system in<i>Plasmodium</i>-infected erythrocytes

Sherling, Emma S.; Ooij, Christiaan van

doi:10.1093/femsre/fuw016

Cited by 52 publications

(61 citation statements)

References 251 publications

(345 reference statements)

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“…One of the most striking features of the PV is the intimate proximity of the PVM and PPM, which is maintained until a very late stage of parasite development when PVM rounding occurs just prior to egress (Glushakova et al, 2018;Sherling & van Ooij, 2016). Additional lateral organisation of this compartment is suggested by the formation of distinct oligomeric arrays of EXP1 and ETRAMPs in the PVM (Spielmann, Gardiner, Beck, Trenholme, & Kemp, 2006) and by the nonuniform distribution of PTEX components as well as PV-targeted exported and nonexported fluorescent fusion reporter proteins, which have been shown to display a punctate distribution in the PV described as a "necklace of beads" (Adisa et al, 2003;Bullen et al, 2012;Charnaud, Jonsdottir, et al, 2018;de Koning-Ward et al, 2009;Riglar et al, 2013;Wickham et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

EXP1 is required for organisation of EXP2 in the intraerythrocytic malaria parasite vacuole

Nessel

Beck

Rayatpisheh

et al. 2020

Cellular Microbiology

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Intraerythrocytic malaria parasites reside within a parasitophorous vacuole membrane (PVM) that closely overlays the parasite plasma membrane. Although the PVM is the site of several transport activities essential to parasite survival, the basis for organisation of this membrane system is unknown. Here, we performed proximity labeling at the PVM with BioID2, which highlighted a group of single‐pass integral membrane proteins that constitute a major component of the PVM proteome but whose function remains unclear. We investigated EXP1, the longest known member of this group, by adapting a CRISPR/Cpf1 genome editing system to install the TetR–DOZI‐aptamers system for conditional translational control. Importantly, although EXP1 was required for intraerythrocytic development, a previously reported in vitro glutathione S‐transferase activity could not account for this essential EXP1 function in vivo. EXP1 knockdown was accompanied by profound changes in vacuole ultrastructure, including apparent increased separation of the PVM from the parasite plasma membrane and formation of abnormal membrane structures. Furthermore, although activity of the Plasmodium translocon of exported proteins was not impacted by depletion of EXP1, the distribution of the translocon pore‐forming protein EXP2 but not the HSP101 unfoldase was substantially altered. Collectively, our results reveal a novel PVM defect that indicates a critical role for EXP1 in maintaining proper organisation of EXP2 within the PVM.

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Section: Introductionmentioning

confidence: 99%

EXP1 is required for organisation of EXP2 in the intraerythrocytic malaria parasite vacuole

Nessel

Beck

Rayatpisheh

et al. 2020

Cellular Microbiology

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“…Phospholipid transfer proteins in Plasmodium are of particular interest as one of the most striking changes induced by the parasite in the host erythrocyte, the site of replication of the parasite during the clinical stage of the disease, is the formation of a large exomembrane system (25). This consists of several different, most likely unconnected, membranous compartments that have various functions within the cell.…”

Section: Introductionmentioning

confidence: 99%

Regulation and Essentiality of the StAR-related Lipid Transfer (START) Domain-containing Phospholipid Transfer Protein PFA0210c in Malaria Parasites

Hill

Ringel

Knuepfer

et al. 2016

Journal of Biological Chemistry

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StAR-related lipid transfer (START) domains are phospholipid- or sterol-binding modules that are present in many proteins. START domain-containing proteins (START proteins) play important functions in eukaryotic cells, including the redistribution of phospholipids to subcellular compartments and delivering sterols to the mitochondrion for steroid synthesis. How the activity of the START domain is regulated remains unknown for most of these proteins. The Plasmodium falciparum START protein PFA0210c (PF3D7_0104200) is a broad-spectrum phospholipid transfer protein that is conserved in all sequenced Plasmodium species and is most closely related to the mammalian START proteins STARD2 and STARD7. PFA0210c is unusual in that it contains a signal sequence and a PEXEL export motif that together mediate transfer of the protein from the parasite to the host erythrocyte. The protein also contains a C-terminal extension, which is very uncommon among mammalian START proteins. Whereas the biochemical properties of PFA0210c have been characterized, the function of the protein remains unknown. Here, we provide evidence that the unusual C-terminal extension negatively regulates phospholipid transfer activity. Furthermore, we use the genetically tractable Plasmodium knowlesi model and recently developed genetic technology in P. falciparum to show that the protein is essential for growth of the parasite during the clinically relevant asexual blood stage life cycle. Finally, we show that the regulation of phospholipid transfer by PFA0210c is required in vivo, and we identify a potential second regulatory domain. These findings provide insight into a novel mechanism of regulation of phospholipid transfer in vivo and may have important implications for the interaction of the malaria parasite with its host cell.

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“…Such TVNs have previously been described in infected RBCs (iRBCs) and in hepatocytes (e.g. reviewed in De Niz et al, 2016;Sherling and van Ooij, 2016). Further compartments of the exomembrane system in iRBCs are the Maureŕs clefts (MCs) and mobile J-dots.…”

Section: Membrane Dynamics and Lipid Turnover In Plasmodial Parasitesmentioning

confidence: 88%

Phospholipases during membrane dynamics in malaria parasites

Flammersfeld

Lang

Flieger

et al. 2018

International Journal of Medical Microbiology

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A B S T R A C TPlasmodium parasites, the causative agents of malaria, display a well-regulated lipid metabolism required to ensure their survival in the human host as well as in the mosquito vector. The fine-tuning of lipid metabolic pathways is particularly important for the parasites during the rapid erythrocytic infection cycles, and thus enzymes involved in lipid metabolic processes represent prime targets for malaria chemotherapeutics. While plasmodial enzymes involved in lipid synthesis and acquisition have been studied in the past, to date not much is known about the roles of phospholipases for proliferation and transmission of the malaria parasite. These phospholipid-hydrolyzing esterases are crucial for membrane dynamics during host cell infection and egress by the parasite as well as for replication and cell signaling, and thus they are considered important virulence factors. In this review, we provide a comprehensive bioinformatic analysis of plasmodial phospholipases identified to date. We further summarize previous findings on the lipid metabolism of Plasmodium, highlight the roles of phospholipases during parasite life-cycle progression, and discuss the plasmodial phospholipases as potential targets for malaria therapy.

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Host cell remodeling by pathogens: the exomembrane system inPlasmodium-infected erythrocytes

Cited by 52 publications

References 251 publications

EXP1 is required for organisation of EXP2 in the intraerythrocytic malaria parasite vacuole

EXP1 is required for organisation of EXP2 in the intraerythrocytic malaria parasite vacuole

Regulation and Essentiality of the StAR-related Lipid Transfer (START) Domain-containing Phospholipid Transfer Protein PFA0210c in Malaria Parasites

Phospholipases during membrane dynamics in malaria parasites

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