A Phosphoinositide-Binding Protein Acts in the Trafficking Pathway of Hemoglobin in the Malaria Parasite Plasmodium falciparum

Mukherjee, Avinaba; Crochetière, Marie-Ève; Sergerie, Audrey; Amiar, Souad; Thompson, L. Alexa; Ebrahimzadeh, Zeinab; Gagnon, Dominic; Lauruol, Florian; Bourgeois, Alice; Galaup, Thomas; Roucheray, Stéphanie; Hallée, Stéphanie; Padmanabhan, Prasad K.; Stahelin, Robert V.; Dacks, Joel B.; Richard, Dave

doi:10.1128/mbio.03239-21

Cited by 12 publications

(14 citation statements)

References 136 publications

(179 reference statements)

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“…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. In previous work we used a quantitative BioID approach to identify proteins in close proximity to K13 and its interactor Eps15 [26].…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

mentioning

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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“…Although we occasionally observe MyoI at or around the BC of extracellular parasites, MyoI foci are widely distributed throughout the cytoplasm, which therefore, only partly supports this hypothesis and needs further attention in the future (Figure 3B) . An additional, more puzzling observation is found in the TgBCC9 ortholog in P. falciparum, named PfPH2, which was associated with a role in microneme exocytosis and localizes to the apical end (Ebrahimzadeh et al, 2019;Mukherjee et al, 2022). As evident from the data assembled here, endocytosis of extracellular parasites might play out at the basal end rather than at the apical end and could be mechanistically related to the microneme secretion defect observed upon coronin depletion in T. gondii (Salamun et al, 2014).…”

Section: Motilitymentioning

confidence: 67%

Toxoplasma gondii’s Basal Complex: The Other Apicomplexan Business End Is Multifunctional

Gubbels

Ferguson

Saha

et al. 2022

Front. Cell. Infect. Microbiol.

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The Apicomplexa are famously named for their apical complex, a constellation of organelles at their apical end dedicated to invasion of their host cells. In contrast, at the other end of the cell, the basal complex (BC) has been overshadowed since it is much less prominent and specific functions were not immediately obvious. However, in the past decade a staggering array of functions have been associated with the BC and strides have been made in understanding its structure. Here, these collective insights are supplemented with new data to provide an overview of the understanding of the BC in Toxoplasma gondii. The emerging picture is that the BC is a dynamic and multifunctional complex, with a series of (putative) functions. The BC has multiple roles in cell division: it is the site where building blocks are added to the cytoskeleton scaffold; it exerts a two-step stretch and constriction mechanism as contractile ring; and it is key in organelle division. Furthermore, the BC has numerous putative roles in ‘import’, such as the recycling of mother cell remnants, the acquisition of host-derived vesicles, possibly the uptake of lipids derived from the extracellular medium, and the endocytosis of micronemal proteins. The latter process ties the BC to motility, whereas an additional role in motility is conferred by Myosin C. Furthermore, the BC acts on the assembly and/or function of the intravacuolar network, which may directly or indirectly contribute to the establishment of chronic tissue cysts. Here we provide experimental support for molecules acting in several of these processes and identify several new BC proteins critical to maintaining the cytoplasmic bridge between divided parasites. However, the dispensable nature of many BC components leaves many questions unanswered regarding its function. In conclusion, the BC in T. gondii is a dynamic and multifunctional structure at the posterior end of the parasite.

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“…The gene knockout of Plasmodium-specific putative phosphoinositide-binding protein (PfPX1) was found to affect the haemoglobin trafficking pathway and made the parasite ART-resistant, suggesting that the haemoglobin trafficking pathway is an essential process for the ART-resistance mechanism. It was also shown that PfPX1 binds to phosphatidylinositol-3-phosphate (PI3P), a molecule that has already been shown to be affected by K13 mutation [15,24]. Taken together, different Fd and ARPS10 alleles might affect the isoprenoid synthesis pathway that leads to insufficient substrates for vesicle formation, especially the haemoglobin vesicular trafficking pathway which is also affected by the K13 mutation and consequently enhances parasite ART-resistance.…”

Section: Discussionmentioning

confidence: 99%

Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum

Kampoun

Srichairatanakool²,

Prommana³

et al. 2022

Malar J

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Background The resistance of Plasmodium falciparum to artemisinin-based (ART) drugs, the front-line drug family used in artemisinin-based combination therapy (ACT) for treatment of malaria, is of great concern. Mutations in the kelch13 (k13) gene (for example, those resulting in the Cys580Tyr [C580Y] variant) were identified as genetic markers for ART-resistant parasites, which suggests they are associated with resistance mechanisms. However, not all resistant parasites contain a k13 mutation, and clearly greater understanding of resistance mechanisms is required. A genome-wide association study (GWAS) found single nucleotide polymorphisms associated with ART-resistance in fd (ferredoxin), arps10 (apicoplast ribosomal protein S10), mdr2 (multidrug resistance protein 2), and crt (chloroquine resistance transporter), in addition to k13 gene mutations, suggesting that these alleles contribute to the resistance phenotype. The importance of the FD and ARPS10 variants in ART resistance was then studied since both proteins likely function in the apicoplast, which is a location distinct from that of K13. Methods The reported mutations were introduced, together with a mutation to produce the k13-C580Y variant into the ART-sensitive 3D7 parasite line and the effect on ART-susceptibility using the 0−3 h ring survival assay (RSA0−3 h) was investigated. Results and conclusion Introducing both fd-D193Y and arps10-V127M into a k13-C580Y-containing parasite, but not a wild-type k13 parasite, increased survival of the parasite in the RSA0−3 h. The results suggest epistasis of arps10 and k13, with arps10-V127M a modifier of ART susceptibility in different k13 allele backgrounds.

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A Phosphoinositide-Binding Protein Acts in the Trafficking Pathway of Hemoglobin in the Malaria Parasite Plasmodium falciparum

Cited by 12 publications

References 136 publications

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

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

Toxoplasma gondii’s Basal Complex: The Other Apicomplexan Business End Is Multifunctional

Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum

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