A Microtubule-Associated Protein Is Essential for Malaria Parasite Transmission

Wichers, Jan Stephan; Binder, Annika M; Mesén-Ramírez, Paolo; Dorner, Lilian Patrick; Safavi, Soraya; Fuchs, Gwendolin; Lenz, Tobias L.; Bachmann, Anna; Wilson, Danny W.; Frischknecht, Friedrich; Gilberger, Tim‐Wolf

doi:10.1128/mbio.03318-22

Cited by 12 publications

(8 citation statements)

References 101 publications

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“…For co-localisation experiments the plasmids p40PX-mCherry [ 54 ], pmCherry-K13_DHODH nmd3 [ 29 ], ama1 PhIL1mCherry [ 136 ] and pGRASPmCherry-BSD nmd3 [ 29 ] were used.…”

Section: Methodsmentioning

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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“…For co-localisation experiments the plasmids p40PX-mCherry [ 54 ], pmCherry-K13_DHODH nmd3 [ 29 ], ama1 PhIL1mCherry [ 136 ] and pGRASPmCherry-BSD nmd3 [ 29 ] were used.…”

Section: Methodsmentioning

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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“…Purified ookinetes were fixed over-night at 4 °C in 2% PFA/2% glutaraldehyde/0.1 M cacodylate buffer and processed as described before ( 60 ). Embedded ookinetes were sectioned to 200 nm-thick sections and imaged on a transmission electron microscope at 200 kV (Tecnai F20 TEM, FEI) equipped with a Eagle 4k x 4k CCD camera (FEI).…”

Section: Methodsmentioning

confidence: 99%

A non-canonical Arp2/3 complex is essential forPlasmodiumDNA segregation and transmission of malaria

Hentzschel,

Jewanski,

Sokolowski

et al. 2023

Preprint

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The malaria-causing parasite Plasmodium has a complex life cycle involving both vertebrate and mosquito hosts. Sexual stages or gametocytes are the only stage competent for transmission to mosquitoes. Formation of flagellated male gametes from gametocytes requires rapid rounds of genome replication. Here we discovered a non-canonical Plasmodium actin-related protein 2/3 (Arp2/3) complex essential for DNA segregation during male gametogenesis. Plasmodium Arp2/3 dynamically localizes within the nucleus to the endomitotic spindles and interacts with a kinetochore protein. Deletion of key Arp2/3 subunits or interfering with actin polymerisation leads to the formation of sub-haploid male gametes and a complete block in transmission through delayed developmental arrest at the oocyst stage. Our work identified an evolutionary divergent protein complex in malaria parasites that offers potential targets for transmission-blocking interventions.

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“…Purified ookinetes were fixed over-night at 4 °C in 2% PFA/2% glutaraldehyde/0.1 M cacodylate buffer and processed as described before 65 . Embedded ookinetes were sectioned to 200 nm-thick sections and imaged on a transmission electron microscope at 200 kV (Tecnai F20 TEM, FEI) equipped with a Eagle 4k x 4k CCD camera (FEI).…”

Section: Ookinete Em Reconstructionsmentioning

confidence: 99%

A non-canonical Arp2/3 complex is essential for Plasmodium DNA segregation and transmission of malaria.

Hentzschel,

Jewanski,

Sokolowski

et al. 2024

Preprint

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Plasmodium parasites, the causative agents of malaria, undergo a crucial development within the mosquito vector, initiated by the formation of male and female gametes from gametocytes. Male gametogenesis involves three rapid rounds of endomitosis followed by a single round of DNA segregation and nuclear division during gamete budding. How the cell organises the segregation of eight genomes from a single octoploid nucleus is currently unknown. Here, we discovered an atypical five-subunit Arp2/3 complex in Plasmodium essential for DNA segregation during male gametogenesis. Unlike the canonical seven-subunit Arp2/3 complex found in other eukaryotes, Plasmodium Arp2/3 localizes to endomitotic spindles and interacts with the kinetochores. Disruption of key Arp2/3 subunits or actin polymerization impedes proper DNA segregation, resulting in the formation of sub-haploid gametes and halting transmission. Our work identified an evolutionary divergent Arp2/3 protein complex in malaria parasites that offers novel insights into its function and potential targets for transmission-blocking interventions.

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A Microtubule-Associated Protein Is Essential for Malaria Parasite Transmission

Cited by 12 publications

References 101 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

A non-canonical Arp2/3 complex is essential forPlasmodiumDNA segregation and transmission of malaria

A non-canonical Arp2/3 complex is essential for Plasmodium DNA segregation and transmission of malaria.

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