Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target

Wagner, Matthias Paulus; Formaglio, Pauline; Gorgette, Olivier; Dziekan, Jerzy Michał; Huon, Christèle; Berneburg, Isabell; Rahlfs, Stefan; Barale, Jean-Christophe; Feinstein, Sheldon I.; Fisher, Aron B.; Ménard, Didier; Bozdech, Zbynek; Amino, Rogério; Touqui, Lhousseine; Chitnis, Chetan E.

doi:10.1016/j.celrep.2022.110923

Cited by 13 publications

(10 citation statements)

References 61 publications

(66 reference statements)

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“…The molecular effectors involved in this process remain poorly characterized. So far VPS45 [ 54 ], Rbsn5 [ 55 ], Rab5b [ 55 ], the phosphoinositide-binding protein PX1 [ 56 ], the host enzyme peroxiredoxin 6 [ 57 ] and K13 and some of its compartment proteins (Eps15, AP2μ, KIC7, UBP1) [ 29 ] have been reported to act at different steps in the endocytic uptake pathway of hemoglobin. While inactivation of VPS45, Rbsn5, Rab5b, PX1 or actin resulted in an accumulation of hemoglobin filled vesicles [ 53 – 56 ], indicative of a block during endosomal transport (late steps in endocytosis), no such vesicles were observed upon inactivation of K13 and its compartment proteins [ 29 ], suggesting a role of these proteins during initiation of endocytosis (early steps in endocytosis).…”

Section: Introductionmentioning

confidence: 99%

The Kelch13 compartment contains highly divergent vesicle trafficking proteins in malaria parasites

Schmidt,

Wichers-Misterek,

Behrens

et al. 2023

PLoS Pathog

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Single amino acid changes in the parasite protein Kelch13 (K13) result in reduced susceptibility of P. falciparum parasites to artemisinin and its derivatives (ART). Recent work indicated that K13 and other proteins co-localising with K13 (K13 compartment proteins) are involved in the endocytic uptake of host cell cytosol (HCCU) and that a reduction in HCCU results in reduced susceptibility to ART. HCCU is critical for parasite survival but is poorly understood, with the K13 compartment proteins among the few proteins so far functionally linked to this process. Here we further defined the composition of the K13 compartment by analysing more hits from a previous BioID, showing that MyoF and MCA2 as well as Kelch13 interaction candidate (KIC) 11 and 12 are found at this site. Functional analyses, tests for ART susceptibility as well as comparisons of structural similarities using AlphaFold2 predictions of these and previously identified proteins showed that vesicle trafficking and endocytosis domains were frequent in proteins involved in resistance or endocytosis (or both), comprising one group of K13 compartment proteins. While this strengthened the link of the K13 compartment to endocytosis, many proteins of this group showed unusual domain combinations and large parasite-specific regions, indicating a high level of taxon-specific adaptation of this process. Another group of K13 compartment proteins did not influence endocytosis or ART susceptibility and lacked detectable vesicle trafficking domains. We here identified the first protein of this group that is important for asexual blood stage development and showed that it likely is involved in invasion. Overall, this work identified novel proteins functioning in endocytosis and at the K13 compartment. Together with comparisons of structural predictions it provides a repertoire of functional domains at the K13 compartment that indicate a high level of adaption of endocytosis in malaria parasites.

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Section: Introductionmentioning

confidence: 99%

The Kelch13 compartment contains highly divergent vesicle trafficking proteins in malaria parasites

Schmidt,

Wichers-Misterek,

Behrens

et al. 2023

PLoS Pathog

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“…Hemoglobin trafficking to the parasite food vacuole is believed to be initiated at membrane invaginations called cytostomes [27,33,39] followed by vesicular transport from the parasite plasma membrane (PPM) to the food vacuole [33,40], likely in an actin-myosin motor dependent manner [39,[41][42][43]. The molecular effectors involved in this process remain poorly characterized and so far only VPS45 [44], the phosphoinositide-binding protein PX1 [45], the host enzyme peroxiredoxin 6 [46] and K13 and some of its compartment proteins (Eps15, AP2µ, KIC7, UBP1) [26] have been reported to act at different steps in the endocytic uptake pathway of hemoglobin. While inactivation of VPS45, PX1 or actin resulted in an accumulation of hemoglobin filled vesicles [43][44][45], indicative of a block during endosomal transport, no such vesicles were observed upon inactivation of K13 and its compartment proteins [26], suggesting a role of these proteins during initiation of endocytosis.…”

Section: Introductionmentioning

confidence: 99%

The Kelch13 compartment is a hub of highly divergent vesicle trafficking proteins in malaria parasites

Schmidt

Wichers

Behrens

et al. 2022

Preprint

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Single amino acid changes in the parasite protein Kelch13 (K13) result in reduced susceptibility ofP. falciparumparasites to Artemisinin and its derivatives (ART). Recent work indicated that K13 and other proteins co-localising with K13 (K13 compartment proteins) are involved in the endocytic uptake of host cell cytosol (HCCU) and that a reduction in HCCU results in ART resistance. HCCU is critical for parasite survival but is poorly understood, with the K13 compartment proteins are among the few proteins so far functionally linked to this process. Here we further defined the composition of the K13 compartment by identifying four novel proteins at this site. Functional analyses, tests for ART susceptibility as well as comparisons of structural similarities using AlphaFold2 predictions of these, and previously identified proteins, showed that canonical vesicle trafficking and endocytosis domains were frequent in proteins involved in resistance and endocytosis, strengthening the link to endocytosis. Despite this, most showed unusual domain combinations and large parasite-specific regions, indicating a high level of taxon-specific adaptation. A second group of proteins did not influence endocytosis or ART resistance and was characterised by a lack of vesicle trafficking domains. We here identified the first essential protein of the second group and showed that it is needed in late-stage parasites. Overall, this work identified novel proteins functioning in endocytosis and at the K13 compartment. Together with comparisons of structural predictions it provides a repertoire of functional domains at the K13 compartment that indicate a high level of adaption of the endocytosis in malaria parasites.

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“…Biosensors were activated with 10 mM nickel sulfate (NiSO 4 , 656895, Sigma) for 180 s and later dipped in buffer (120 s). PvDBPII variant SalI or PvDBPII PvW1 were immobilized via His tag at 5 μg/ml for 600 s. A mammalian cytosolic protein, peroxiredoxin 6 (PRDX6) 49 , was loaded at 3 μg/ml to pre-charged NTA biosensors for 600 s as a reference biosensor (negative control). Loaded biosensors were tested for binding to test sera in the following steps: baseline (60 s in buffer), association step (600 s in serum dilutions) and dissociation step (600 s in buffer).…”

Section: Methodsmentioning

confidence: 99%

PvDBPII elicits multiple antibody-mediated mechanisms that reduce growth in a Plasmodium vivax challenge trial

Martinez,

White,

Guillotte-Blisnick

et al. 2024

npj Vaccines

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The receptor-binding domain, region II, of the Plasmodium vivax Duffy binding protein (PvDBPII) binds the Duffy antigen on the reticulocyte surface to mediate invasion. A heterologous vaccine challenge trial recently showed that a delayed dosing regimen with recombinant PvDBPII SalI variant formulated with adjuvant Matrix-MTM reduced the in vivo parasite multiplication rate (PMR) in immunized volunteers challenged with the Thai P. vivax isolate PvW1. Here, we describe extensive analysis of the polyfunctional antibody responses elicited by PvDBPII immunization and identify immune correlates for PMR reduction. A classification algorithm identified antibody features that significantly contribute to PMR reduction. These included antibody titre, receptor-binding inhibitory titre, dissociation constant of the PvDBPII-antibody interaction, complement C1q and Fc gamma receptor binding and specific IgG subclasses. These data suggest that multiple immune mechanisms elicited by PvDBPII immunization are likely to be associated with protection and the immune correlates identified could guide the development of an effective vaccine for P. vivax malaria. Importantly, all the polyfunctional antibody features that correlated with protection cross-reacted with both PvDBPII SalI and PvW1 variants, suggesting that immunization with PvDBPII should protect against diverse P. vivax isolates.

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Human peroxiredoxin 6 is essential for malaria parasites and provides a host-based drug target

Cited by 13 publications

References 61 publications

The Kelch13 compartment contains highly divergent vesicle trafficking proteins in malaria parasites

The Kelch13 compartment contains highly divergent vesicle trafficking proteins in malaria parasites

The Kelch13 compartment is a hub of highly divergent vesicle trafficking proteins in malaria parasites

PvDBPII elicits multiple antibody-mediated mechanisms that reduce growth in a Plasmodium vivax challenge trial

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