PbAP2-FG2 and PbAP2R-2 function together as a transcriptional repressor complex essential for Plasmodium female development

Nishi, Tsubasa; Kaneko, Ikuyo; Iwanaga, Shiroh

doi:10.1371/journal.ppat.1010890

Cited by 9 publications

(15 citation statements)

References 69 publications

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“…The target genes in ‘female-specific functions’ are written according to their belongings: unique to sAP2-FG, common, and unique to cAP2-FG. The assignment of these genes into each subgroup was based on functional annotation in Plasmo DB and the following references(16)(24)(25)(26)(27)(28)(29)(30)(31)(14)(32)(33)(18)(34)(35)(36)(37)(38)(39)(40)(41)(42). D. IGV images from the ChIP-seq data of AP2-G, PFG, and sAP2-FG in the upstream region of PFG .…”

Section: Resultsmentioning

confidence: 99%

Coordinated regulation of gene expression inPlasmodiumfemale gametocytes by two transcription factors

Murata

Nishi

Kaneko

et al. 2023

Preprint

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Gametocytes play key roles in the Plasmodium lifecycle. They are essential for sexual reproduction as precursors of the gametes. They also play an essential role in parasite transmission to mosquitoes. Elucidation of the gene regulation at this stage is essential for understanding these two processes at the molecular level and for developing new strategies to break the parasite life cycle. We identified a novel Plasmodium transcription factor (TF), designated as a partner of AP2-FG or PFG. In this paper, we report that this TF regulates the gene expression in female gametocytes in concert with another female-specific TF AP2-FG. Upon the disruption of PFG, majority of female-specific genes were significantly downregulated, and female gametocyte lost the ability to produce ookinetes. ChIP-seq analysis showed that it was located in the same position as AP2-FG, indicating that these two TFs form a complex. ChIP-seq analysis of PFG in AP2-FG-disrupted parasites and ChIP-seq analysis of AP2-FG in PFG-disrupted parasites demonstrated that PFG mediates the binding of AP2-FG to the ten-base motif and that AP2-FG binds another motif, GCTCA, in the absence of PFG. In promoter assays, this five-base motif was identified as another female-specific cis-acting element. Genes under the control of the two forms of AP2-FG, with or without PFG, partly overlapped; however, each form had target preferences. These results suggested that combinations of these two forms generate various expression patterns among the extensive genes expressed in female gametocytes.

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Section: Resultsmentioning

confidence: 99%

Coordinated regulation of gene expression inPlasmodiumfemale gametocytes by two transcription factors

Murata

Nishi

Kaneko

et al. 2023

Preprint

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“…Interestingly, an ACDC domain has recently been identified in a Plasmodium protein (AP2R-2) that lacks functional AP2 domains (Yuda et al ., 2021). In P. berghei , PbAP2R-2 has been shown to interact with the ApiAP2 protein PbAP2-FG2, which also contains an ACDC domain, to form a transcriptional repressor complex (Nishi et al ., 2023), supporting the hypothesis that the ACDC domain mediates protein-protein interactions.…”

Section: Discussionmentioning

confidence: 99%

Structural characterization of the ACDC domain from ApiAP2 proteins of the malaria parasite

Le Berre,

Tubiana,

Reuterswärd Waldner

et al. 2024

Preprint

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The Apicomplexan AP2 (ApiAP2) proteins are the best characterized family of DNA-binding proteins in the malaria parasite. Apart from the AP2 DNA-binding domain, there is little sequence similarity between ApiAP2 proteins and no other functional domains have been extensively characterized. One protein domain, which is present in a subset of the ApiAP2 proteins, is the conserved AP2-coincident domain mostly at the C-terminus (ACDC domain). Here we solved for the first time the crystal structure of the ACDC domain from two distinctPlasmodium falciparumApiAP2 proteins and one orthologue fromP. vivax, revealing a non-canonical four-helix bundle. Despite little sequence conservation between the ACDC domains from the two proteins, the structures are remarkably similar and do not resemble that of any other known protein domains. Due to their unique protein architecture and lack of homologues in the human genome, we performedin silicodocking calculations against a library of known antimalarial compounds and we identified a small molecule that can potentially bind to any Apicomplexan ACDC domain within a pocket highly conserved amongst ApiAP2 proteins. Inhibitors based on this compound would disrupt the function of the ACDC domain and thus of the ApiAP2 proteins containing it, providing a new therapeutic window for targeting the malaria parasite and other Apicomplexans.

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“…FD3 and MD4/PfARID show a high degree of connectivity to the female and male clusters, respectively, and play a role in gametocyte fertility in P. berghei and P. falciparum (10,28,35,36). Disruption of HMGB2, AP2-O3, and PF3D7_0522900 leads to reduced growth in the ookinete or oocyst stages, indicating that downstream players of these factors may affect transmission (37)(38)(39)(40)(41). Finally, we find an association of the male cluster and AP2-G5, which is known to regulate AP2-G and is essential for gametocyte maturation (1,42).…”

Section: Inferring Interactions Of Transcription Factors With Sexual ...mentioning

confidence: 99%

A single cell atlas of sexual development in Plasmodium falciparum

Dogga,

Rop,

Cudini

et al. 2024

Science

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The developmental decision made by malaria parasites to become sexual underlies all malaria transmission. Here, we describe a rich atlas of short- and long-read single-cell transcriptomes of over 37,000 Plasmodium falciparum cells across intraerythrocytic asexual and sexual development. We used the atlas to explore transcriptional modules and exon usage along sexual development and expanded it to include malaria parasites collected from four Malian individuals naturally infected with multiple P. falciparum strains. We investigated genotypic and transcriptional heterogeneity within and among these wild strains at the single-cell level, finding differential expression between different strains even within the same host. These data are a key addition to the Malaria Cell Atlas interactive data resource, enabling a deeper understanding of the biology and diversity of transmission stages.

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PbAP2-FG2 and PbAP2R-2 function together as a transcriptional repressor complex essential for Plasmodium female development

Cited by 9 publications

References 69 publications

Coordinated regulation of gene expression inPlasmodiumfemale gametocytes by two transcription factors

Coordinated regulation of gene expression inPlasmodiumfemale gametocytes by two transcription factors

Structural characterization of the ACDC domain from ApiAP2 proteins of the malaria parasite

A single cell atlas of sexual development in Plasmodium falciparum

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