The Mu Subunit of Plasmodium falciparum Clathrin-Associated Adaptor Protein 2 Modulates
            <i>In Vitro</i>
            Parasite Response to Artemisinin and Quinine

Henriques, Gisela; Schalkwyk, Donelly A. van; Burrow, Rebekah; Warhurst, David C.; Thompson, Eloise; Baker, David A.; Fidock, David A.; Hallett, Rachel; Flueck, Christian; Sutherland, Colin J.

doi:10.1128/aac.04067-14

Cited by 45 publications

(42 citation statements)

References 25 publications

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“…Our recent data indicate that P. falciparum expressing variants of the subunit of AP-2 display reduced susceptibility to artemisinin in vivo and in vitro (38)(39)(40), potentially linking endocytosis to resistance. Given the importance of hemoglobin uptake to parasite survival and drug action in Plasmodium, the endocytic function of AP-2 across taxa, and the confirmed role of AP-2 in artemisinin susceptibility, we sought evidence that AP-2 contributes to clathrin-mediated hemoglobin uptake during asexual parasite development in vitro.…”

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confidence: 90%

The Plasmodium falciparum Artemisinin Susceptibility-Associated AP-2 Adaptin μ Subunit is Clathrin Independent and Essential for Schizont Maturation

Henrici

Edwards

Zoltner

et al. 2020

mBio

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The efficacy of current antimalarial drugs is threatened by reduced susceptibility of Plasmodium falciparum to artemisinin, associated with mutations in pfkelch13. Another gene with variants known to modulate the response to artemisinin encodes the μ subunit of the AP-2 adaptin trafficking complex. To elucidate the cellular role of AP-2μ in P. falciparum, we performed a conditional gene knockout, which severely disrupted schizont organization and maturation, leading to mislocalization of key merozoite proteins. AP-2μ is thus essential for blood-stage replication. We generated transgenic P. falciparum parasites expressing hemagglutinin-tagged AP-2μ and examined cellular localization by fluorescence and electron microscopy. Together with mass spectrometry analysis of coimmunoprecipitating proteins, these studies identified AP-2μ-interacting partners, including other AP-2 subunits, the K10 kelch-domain protein, and PfEHD, an effector of endocytosis and lipid mobilization, but no evidence was found of interaction with clathrin, the expected coat protein for AP-2 vesicles. In reverse immunoprecipitation experiments with a clathrin nanobody, other heterotetrameric AP-complexes were shown to interact with clathrin, but AP-2 complex subunits were absent. IMPORTANCE We examine in detail the AP-2 adaptin complex from the malaria parasite Plasmodium falciparum. In most studied organisms, AP-2 is involved in bringing material into the cell from outside, a process called endocytosis. Previous work shows that changes to the μ subunit of AP-2 can contribute to drug resistance. Our experiments show that AP-2 is essential for parasite development in blood but does not have any role in clathrin-mediated endocytosis. This suggests that a specialized function for AP-2 has developed in malaria parasites, and this may be important for understanding its impact on drug resistance.

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confidence: 90%

The Plasmodium falciparum Artemisinin Susceptibility-Associated AP-2 Adaptin μ Subunit is Clathrin Independent and Essential for Schizont Maturation

Henrici

Edwards

Zoltner

et al. 2020

mBio

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“…Analysis of parasite isolates from ACT-treated Kenyan children suggested an increased prevalence of S160N/T mutations in PfAP2-μ (PF3D7_1218300) or a E1528D mutation in PfUBP1 in parasites surviving ACT treatment [81]. Expression of an extra copy of pfap2-mu harboring a S160N mutation increased P. falciparum in vitro sensitivity to chloroquine and quinine [82]. A separate study associated the HECT E3 ligase P. falciparum ubiquitin transferase (PfUT) (PF3D7_0704600) variant harboring a Y1387F mutation, in the presence of the K76T mutation in the P. falciparum chloroquine resistance transporter (PfCRT), with quinine resistance [83].…”

Section: The Roles Of Ubiquitin Ligases and Deubiquitinating Enzymes mentioning

confidence: 99%

Protein Degradation Systems as Antimalarial Therapeutic Targets

Fidock

Bogyo

2017

Trends in Parasitology

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Artemisinin (ART)-based combination therapies are the most efficacious treatment of non-complicated Plasmodium falciparum infection. Alarmingly, P. falciparum strains have acquired resistance to ART in Southeast Asia and Africa. ART creates widespread protein and lipid damage inside intra-erythrocytic parasites, necessitating macromolecule degradation. The proteasome is the main engine of Plasmodium protein degradation. Indeed, proteasome inhibition and ART synergized in ART-resistant parasites. Moreover, ubiquitin modification is associated with resistance to multiple antimalarials. Targeting the ubiquitin-proteasome system, therefore, is an attractive avenue to combat drug resistance. Here, we review recent advances leading to specific targeting of the Plasmodium proteasome. We also highlight the potential for targeting other non-proteasomal protein degradation systems as an additional strategy to disrupt protein homeostasis.

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“…Additional polymorphisms ( dhfr and dhps ) for sulfadoxine-pyrimethamine and polymorphism of P. falciparum multidrug resistance protein 1 ( pfmdr1 ) are associated with resistance to chloroquine, mefloquine, quinine, and artemisinin [30]. Novel loci such as encoding the mu chain of the adopter protein 2 (ap2-mu), P. falciparum ap2-mu (Pfap2-mu) homologue [27], gene mutations encoding pfmdr1 , and sarco-endoplasmic reticulum calcium ATPase6 (PfSERCA) [31] may be associated with antimalarial resistance. Emerging evidence shows that pfmdr 1 , pfcrt , and pf3d7-1343700 Kelch propeller (K13-propeller) mutations are potential markers indicating that P. falciparum is developing resistance to artemisinin and its derivatives [32, 33].…”

Section: Pharmacological Approachesmentioning

confidence: 99%

Alternatives to currently used antimalarial drugs: in search of a magic bullet

Bhagavathula

Elnour²,

Shehab

2016

Infect Dis Poverty

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Malaria is a major cause of morbidity and mortality in many African countries and parts of Asia and South America. Novel approaches to combating the disease have emerged in recent years and several drug candidates are now being tested clinically. However, it is long before these novel drugs can hit the market, especially due to a scarcity of safety and efficacy data.To reduce the malaria burden, the Medicines for Malaria Venture (MMV) was established in 1999 to develop novel medicines through industry and academic partners’ collaboration. However, no reviews were focused following various preclinical and clinical studies published since the MMV initiation (2000) to till date.We identify promising approaches in the global portfolio of antimalarial medicines, and highlight challenges and patient specific concerns of these novel molecules. We discuss different clinical studies focusing on the evaluation of novel drugs against malaria in different human trials over the past five years.The drugs KAE609 and DDD107498 are still being evaluated in Phase I trials and preclinical developmental studies. Both the safety and efficacy of novel compounds such as KAF156 and DSM265 need to be assessed further, especially for use in pregnant women. Synthetic non-artemisinin ozonides such as OZ277 raised concerns in terms of its insufficient efficacy against high parasitic loads. Aminoquinoline-based scaffolds such as ferroquine are promising but should be combined with good partner drugs for enhanced efficacy. AQ-13 induced electrocardiac events, which led to prolonged QTc intervals. Tafenoquine, the only new anti-relapse scaffold for patients with a glucose-6-phosphate dehydrogenase deficiency, has raised significant concerns due to its hemolytic activity. Other compounds, including methylene blue (potential transmission blocker) and fosmidomycin (DXP reductoisomerase inhibitor), are available but cannot be used in children.At this stage, we are unable to identify a single magic bullet against malaria. Future studies should focus on effective single-dose molecules that can act against all stages of malaria in order to prevent transmission. Newer medicines have also raised concerns in terms of efficacy and safety. Overall, more evidence is needed to effectively reduce the current malaria burden. Treatment strategies that target the blood stage with transmission-blocking properties are needed to prevent future drug resistance.Electronic supplementary materialThe online version of this article (doi:10.1186/s40249-016-0196-8) contains supplementary material, which is available to authorized users.

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The Mu Subunit of Plasmodium falciparum Clathrin-Associated Adaptor Protein 2 Modulates In Vitro Parasite Response to Artemisinin and Quinine

Cited by 45 publications

References 25 publications

The Plasmodium falciparum Artemisinin Susceptibility-Associated AP-2 Adaptin μ Subunit is Clathrin Independent and Essential for Schizont Maturation

The Plasmodium falciparum Artemisinin Susceptibility-Associated AP-2 Adaptin μ Subunit is Clathrin Independent and Essential for Schizont Maturation

Protein Degradation Systems as Antimalarial Therapeutic Targets

Alternatives to currently used antimalarial drugs: in search of a magic bullet

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