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

ABSTRACT: 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 mosquito transmission. Gametogenesis of the male gametocyte requires rapid rounds of genome replication to form flagellated gametes. Here, we describe the discovery of 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 spindle 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Plasmodium Berghei

SUBMITTER: Marcin Luzarowski

LAB HEAD: Franziska Hentzschel

PROVIDER: PXD051260 | Pride | 2025-04-22

REPOSITORIES: Pride

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			Action	DRS
	Q25070-23-192-03-48.msf	Msf
	Q25070-23-192-03.raw	Raw
	Q25070-23-192-06.raw	Raw
	Q25070-23-192-09.raw	Raw
	Q25070-23-192-12.raw	Raw

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Similar Datasets

An atypical Arp2/3 complex is required for Plasmodium DNA segregation and transmission of malaria.

Project description:Plasmodium parasites, the causative agents of malaria, undergo crucial developments 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 into eight haploid gametes is currently unknown. Here, we discovered an atypical five-subunit Arp2/3 complex in Plasmodium important for correct 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 a kinetochore-associated protein. Disruption of key Arp2/3 subunits or actin polymerization interferes with kinetochore-spindle association, resulting in the formation of sub-haploid gametes and halting transmission. Our work identified an evolutionary divergent Arp2/3 protein complex in malaria parasites, offers novel insights into gametogenesis, and uncovers potential targets for transmission-blocking interventions.

2025-04-22 | PXD060997 | Pride

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

Project description: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 mosquito transmission. Gametogenesis of the male gametocyte requires rapid rounds of genome replication to form flagellated gametes. Here, we describe the discovery of 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 spindle 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.

2025-04-22 | PXD046181 | Pride

CDPK4 is a pleiotropic regulator controlling the atypical Plasmodium cell cycle during mosquito transmission

Project description:Transmission of malaria parasites from humans to the mosquito vector exclusively relies on the sexual reproduction of the parasite within the mosquito blood meal. Upon ingestion, Plasmodium male gametocyte undergoes explosive development: within 10 minutes, it completes three rounds of genome replication and endomitosis, assembles eight axonemes, and emerges from the host red blood cell. The plant-like calcium-dependent protein kinase 4 (CDPK4) was previously shown to be essential for male gametogenesis placing this kinase as an attractive drug target to block malaria transmission. Here we have identified and resolved three distinct molecular functions of CDPK4 during male gametogenesis. Activity of a myristoylated isoform is first required up to 20 seconds after activation to load the Mini-Chromosome Maintenance complex onto origins of replication. This role is partially mediated by a conserved protein belonging to the SAPS-domain family which is involved in the G1 to S-phase transition in eukaryotes. At the same time, activity of myristoylated CDPK4 is required to phosphorylate a Plasmodium-specific microtubule-associated protein necessary for mitotic spindle assembly. Finally, activity of a short non-myristoylated isoform of CDPK4 is essential seconds prior to completion of cytokinesis and the activation of male gamete motility. This late role has been linked to another Plasmodium-specific protein that is incorporated into axonemes during gametogenesis. This study reveals how a kinase of a protist parasite integrates and transduces multiple signals with a high spatiotemporal resolution to control both evolutionarily conserved and Plasmodium-specific biological processes.

2017-05-24 | PXD005884 | Pride

RNA-seq analyses of gene expression changes in the salivary glands of Anopheles gambiae elicited by Plasmodium berghei infection

Project description:Salivary glands are the only mosquito tissue invaded by Plasmodium sporozoites being a key stage for the effective parasite transmission and maturation, making knowledge regarding Anopheles sialome highly relevant to understand this process. In this study, we report for the first time a transcriptomic analysis using RNA-seq of An. gambiae infected by P. berghei.

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Sub-minute phosphoregulation of cell-cycle systems during Plasmodium gamete formation revealed by a high-resolution time course

Project description:As a first step in the transmission of malaria, Plasmodium parasites ingested by a mosquito must rapidly initiate a gametogenesis process prior to sexual reproduction. The phosphorylation-based signalling mechanisms underlying the initiation of this process remain largely unmapped. We have measured a high-resolution time course of phosphorylation in P. berghei gametocytes during the first minute of gametogenesis to elucidate the scope and dynamics of the response. The data reveals rapid phosphoregulation of microtubule motor proteins and DNA replication initiation proteins within the first 18 s and of DNA replication machinery by 60 s. The data also implicate several protein kinases and phosphatases in the gametogenesis signalling pathway. Through gene knock-out experiments, we verify that the protein kinases CDPK4 and SRPK1 have distinct influences over the phosphorylation of similar downstream targets. Together, the results show that key cell-cycle systems related to both replication and mitosis undergo simultaneous, rapid phosphoregulation.

2017-11-29 | PXD006266 | Pride

Deciphering the kinesin-8B role during Plasmodium berghei gametogenesis by a proteomic approach

Project description:We focused on the iTRAQ-based quantitative proteomic characterization of rodent parasite Plasmodium berghei mutants with disrupted kinesin-8B gene compared to wild type within the gamete differentiation. Time-course analyses were performed 7 and 15 min after gametogenesis induction (Time 0).

2021-04-17 | PXD020911 | Pride

Dynamic molecular events associated to Plasmodium berghei gametogenesis through proteomic approach

Project description:We carried out a iTRAQ-based quantitative proteomic insight into the rodent parasite Plasmodium berghei gamete morphogenesis providing valuable time course data. Time-course analyses were performed 7 and 15 min after gametogenesis induction (Time 0).

2020-08-17 | PXD020892 | Pride

scRNA-seq of rodent malaria parasites (P. berghei) and their host cells in spleen, bone marrow and blood

Project description:The malaria parasite Plasmodium replicates and differentiates in red blood cells of its host. The erythropoietic niches (spleen and bone marrow) are important but poorly understood reservoirs of asexual replication and sexual development. We aimed to understand how the parasite adapts to its host organ and a host cell level. For this, we performed single-cell RNA-seq (scRNA-seq) analysis on host and parasite cells derived from spleen, blood and bone marrow. Organs were harvested from two infected and one uninfected mice and parasite cells were enriched to about 50% by flow sorting (infected samples only). To identify host cells by surface expression (CITE-seq), cells were stained with barcoded antibodies targeting CD44 and CD71. Droplet-based scRNA-seq of these samples was performed using 10X genomics technology and cDNA was sequenced on Illumina.

2021-11-30 | E-MTAB-10800 | biostudies-arrayexpress

A Protein Kinase G-interacting protein regulates critical calcium signals in malaria parasites (phosphoproteomic)

Project description:In malaria parasites, cGMP signalling is mediated by a single cGMP-dependent protein kinase (PKG). One of the major functions of PKG is to control calcium signals essential for the parasite to exit red blood cells or for the transmission of the gametocyte stages to the mosquito. However, how PKG controls these signals in the absence of known second messenger-dependent calcium channels or scaffolding proteins remains a mystery. Here we use pull-down approaches to identify a PKG partner protein in both Plasmodium falciparum schizonts and P. berghei gametocytes. This partner, named ICM1, is a polytopic membrane protein with homologies to transporters and calcium channels, raising the possibility of a direct functional link between PKG and calcium homeostasis. Phosphoproteomic analyses in both Plasmodium species highlight a densely phosphorylated region of ICM1 with multiple phosphorylation events dependent on PKG activity. Conditional disruption of the P. falciparum ICM1 gene results in reduced cGMP-dependent calcium mobilisation associated with defective egress and invasion. Stage-specific depletion of ICM1 in P. berghei gametocytes blocks gametogenesis due to the inability of mutant parasites to mobilise intracellular calcium upon PKG activation. These results provide us with new insights into the atypical calcium homeostasis in malaria parasites

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Proteomic analysis of the Plasmodium male gamete reveals a key role for glycolysis in flagellar motility

Project description:Gametogenesis and fertilization play crucial roles in malaria transmission. While male gametes are thought to be amongst the simplest eukaryotic cells and are proven targets of transmission blocking immunity, little is known about their molecular organization. For example, the pathways of energy metabolism that power motility, a feature that facilitates gamete encounter and fertilization, is unknown. To gain more insight into male gamete, we performed the first proteomic analysis of purified Plasmodium berghei microgametes. We recovered 615 proteins, which include all male gamete proteins described thus far. Amongst the most abundant proteins were the 11 enzymes of the glycolytic pathway. We localized the hexose transporter to the gamete plasma membrane and show that microgamete motility can be suppressed effectively by inhibitors of this transporter, and of the glycolytic pathway. Taken together, these results suggest that glycolysis is the exclusive source of energy for microgamete motility. Considering that this proteome provides a unique platform for the understanding of the original features of the male gamete, we discuss not only the mitochondria-independent energy metabolism but also flagellar structure and intra-flagellar transport-independent assembly, another divergent feature of these cells.

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