A genetic screen in rodent malaria parasites identifies five new apicoplast putative membrane transporters, one of which is essential in human malaria parasites

Sayers, Claire P.; Mollard, Vanessa; Buchanan, Hayley D.; McFadden, Geoffrey I.; Goodman, Christopher D.

doi:10.1111/cmi.12789

Cited by 35 publications

(49 citation statements)

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“…Fortuitously, while this manuscript was in preparation, 7 new apicoplast membrane proteins in P . berghei were validated by Sayers and colleagues [ 43 ]. Of these, apicoplast BioID identified the P .…”

Section: Resultsmentioning

confidence: 99%

“…We expected that these proteins might be important for apicoplast biology, as ABCB-family proteins are integral membrane proteins that typically act as small molecule transporters, and ABCF-family proteins, which do not contain transmembrane domains, are typically involved in translation regulation [ 47 , 48 ]. We pursued reverse genetic characterization of ABCB7 (PF3D7_1209900) and ABCF1 (PF3D7_0813700), as the essentiality of ABCB3 and ABCB4 has been previously studied [ 43 , 49 ].…”

Section: Resultsmentioning

confidence: 99%

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Integrative proteomics and bioinformatic prediction enable a high-confidence apicoplast proteome in malaria parasites

et al. 2018

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Malaria parasites (Plasmodium spp.) and related apicomplexan pathogens contain a nonphotosynthetic plastid called the apicoplast. Derived from an unusual secondary eukaryote–eukaryote endosymbiosis, the apicoplast is a fascinating organelle whose function and biogenesis rely on a complex amalgamation of bacterial and algal pathways. Because these pathways are distinct from the human host, the apicoplast is an excellent source of novel antimalarial targets. Despite its biomedical importance and evolutionary significance, the absence of a reliable apicoplast proteome has limited most studies to the handful of pathways identified by homology to bacteria or primary chloroplasts, precluding our ability to study the most novel apicoplast pathways. Here, we combine proximity biotinylation-based proteomics (BioID) and a new machine learning algorithm to generate a high-confidence apicoplast proteome consisting of 346 proteins. Critically, the high accuracy of this proteome significantly outperforms previous prediction-based methods and extends beyond other BioID studies of unique parasite compartments. Half of identified proteins have unknown function, and 77% are predicted to be important for normal blood-stage growth. We validate the apicoplast localization of a subset of novel proteins and show that an ATP-binding cassette protein ABCF1 is essential for blood-stage survival and plays a previously unknown role in apicoplast biogenesis. These findings indicate critical organellar functions for newly discovered apicoplast proteins. The apicoplast proteome will be an important resource for elucidating unique pathways derived from secondary endosymbiosis and prioritizing antimalarial drug targets.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Integrative proteomics and bioinformatic prediction enable a high-confidence apicoplast proteome in malaria parasites

et al. 2018

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“…These studies have for the most part focused on essentiality and growth rate phenotypes in the asexual blood stage of the parasite and have ranged from those which specifically targeted subsets of transporter genes to the large‐scale knockout screen of 2578 P. berghei genes (Bushell et al ., ). The transporters targeted by the small‐scale screens have included the genes encoding 35 ‘orphan transporters’ (Kenthirapalan et al ., ), ATP‐binding cassette (ABC) type pumps (Rijpma et al ., ), and transporters predicted to localise to the membranes of the apicoplast (Sayers et al ., ).…”

Section: The Plasmodium Transportomementioning

confidence: 97%

“…IPP must traverse the four membranes of the apicoplast to reach the cytosol, but relatively little is understood about the transport processes that occur across these membranes, nor has the apicoplast protein(s) responsible for transporting IPP been identified. One candidate is the apicoplast resident DMT2 (a putative drug/metabolite transporter), which is essential in the asexual blood stage and has been shown to fulfil a crucial function in the maintenance of the organelle, potentially through performing a core housekeeping role (Sayers et al ., ). Given that precedents exist for the localisation of MC proteins to plastids (Palmieri & Monne, ), it is also possible that one of the essential MC genes ( mc2 , mc3 , mc5 , mc6 , or tpc ) encodes the parasite's IPP transporter.…”

Section: New Insights Into Plasmodium Biologymentioning

confidence: 97%

The transportome of the malaria parasite

Martin

2019

Biological Reviews

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Membrane transport proteins, also known as transporters, control the movement of ions, nutrients, metabolites, and waste products across the membranes of a cell and are central to its biology. Proteins of this type also serve as drug targets and are key players in the phenomenon of drug resistance. The malaria parasite has a relatively reduced transportome, with only approximately 2.5% of its genes encoding transporters. Even so, assigning functions and physiological roles to these proteins, and ascertaining their contributions to drug action and drug resistance, has been very challenging. This review presents a detailed critique and synthesis of the disruption phenotypes, protein subcellular localisations, protein functions (observed or predicted), and links to antimalarial drug resistance for each of the parasite's transporter genes. The breadth and depth of the gene disruption data are particularly impressive, with at least one phenotype determined in the parasite's asexual blood stage for each transporter gene, and multiple phenotypes available for 76% of the genes. Analysis of the curated data set revealed there to be relatively little redundancy in the Plasmodium transportome; almost two‐thirds of the parasite's transporter genes are essential or required for normal growth in the asexual blood stage of the parasite, and this proportion increased to 78% when the disruption phenotypes available for the other parasite life stages were included in the analysis. These observations, together with the finding that 22% of the transportome is implicated in the parasite's resistance to existing antimalarials and/or drugs within the development pipeline, indicate that transporters are likely to serve, or are already serving, as drug targets. Integration of the different biological and bioinformatic data sets also enabled the selection of candidates for transport processes known to be essential for parasite survival, but for which the underlying proteins have thus far remained undiscovered. These include potential transporters of pantothenate, isoleucine, or isopentenyl diphosphate, as well as putative anion‐selective channels that may serve as the pore component of the parasite's ‘new permeation pathways’. Other novel insights into the parasite's biology included the identification of transporters for the potential development of antimalarial treatments, transmission‐blocking drugs, prophylactics, and genetically attenuated vaccines. The syntheses presented herein set a foundation for elucidating the functions and physiological roles of key members of the Plasmodium transportome and, ultimately, to explore and realise their potential as therapeutic targets.

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“…During invasion apicomplexan parasites also form a parasitophorous vacuole membrane (PVM) that surrounds the intracellular parasite [3]. Many also contain a novel organelle called the apicoplast, which is homologous to the chloroplast of plants, and harbours critical metabolic pathways that are typical of plastid function such as type II fatty acid biosynthesis, isoprenoid biosynthesis, and haem biosynthesis [4,5]. Apicomplexan parasites undergo highly specialised life cycles, which consist of both asexual and sexual reproductive stages.…”

Section: Introduction Apicomplexansmentioning

confidence: 99%

Transmembrane solute transport in the apicomplexan parasite Plasmodium

Staines

Moore

Slavic

et al. 2017

Emerging Topics in Life Sciences

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Apicomplexa are a large group of eukaryotic, single-celled parasites, with complex life cycles that occur within a wide range of different microenvironments. They include important human pathogens such as Plasmodium, the causal agent of malaria, and Toxoplasma, which causes toxoplasmosis most often in immunocompromised individuals. Despite environmental differences in their life cycles, these parasites retain the ability to obtain nutrients, remove waste products, and control ion balances. They achieve this flexibility by relying on proteins that can deliver and remove solutes. This reliance on transport proteins for essential functions makes these pathways excellent potential targets for drug development programmes. Transport proteins are frequently key mediators of drug resistance by their ability to remove drugs from their sites of action. The study of transport processes mediated by integral membrane proteins and, in particular, identification of their physiological functions and localisation, and differentiation from host orthologues has already established new validated drug targets. Our understanding of how apicomplexan parasites have adapted to changing environmental challenges has also increased through the study of their transporters. This brief introduction to membrane transporters of apicomplexans highlights recent discoveries focusing on Plasmodium and emphasises future directions.

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A genetic screen in rodent malaria parasites identifies five new apicoplast putative membrane transporters, one of which is essential in human malaria parasites

Cited by 35 publications

References 68 publications

Integrative proteomics and bioinformatic prediction enable a high-confidence apicoplast proteome in malaria parasites

Integrative proteomics and bioinformatic prediction enable a high-confidence apicoplast proteome in malaria parasites

The transportome of the malaria parasite

Transmembrane solute transport in the apicomplexan parasite Plasmodium

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