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The P. falciparum orthologue of Male Development Protein 3 is a Male-associated regulator of translation initiation or enhancement [CLIP-Seq]

ABSTRACT: Sex determination and development of Plasmodium gametocytes is critical to the transmission of malaria parasites and involves a complex interplay of multiple molecular factors. Here, we characterized the P. falciparum gene syntenic to P. berghei MD3- pf3d7_0315600. This protein contains a non-classical CCCH zinc-finger domain and Lysine-Proline rich domain associated with ribosome receptors, suggesting a role in mRNA regulation. We investigated the function of PfMD3-3xHA using in vivo using crosslinked RNA-Protein interaction capture followed by RNA-sequencing (CLIP-seq) to determine its RNA targets in both early (stage II) and late (stage IV-V) development of gametocytes. We found that these bound mRNA targets show decreased protein levels in a genetic knockout of PfMD3, suggesting a role for PfMD3 in translational processing. We then propose that PfMD3 functions as a Male Associated Regulator of Translation Initiation or Enhancement (MARTIE) in the human malaria parasite P. falciparum.

ORGANISM(S): Plasmodium falciparum

PROVIDER: GSE267362 | GEO | 2024/09/01

REPOSITORIES: GEO

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The P. falciparum orthologue of Male Development Protein 3 is a Male-associated regulator of translation initiation or enhancement [RNA-Seq]

Project description:Sex determination and development of Plasmodium gametocytes is critical to the transmission of malaria parasites and involves a complex interplay of multiple molecular factors. Here, we characterized the P. falciparum gene syntenic to P. berghei MD3- pf3d7_0315600. This protein contains a non-classical CCCH zinc-finger domain and Lysine-Proline rich domain associated with ribosome receptors, suggesting a role in mRNA regulation. Disruption of PfMD3 causes a pronounced defect in male gametogenesis which severely decreases parasite transmission to mosquitoes but does not affect female gamete production. We show that abrogation of PfMD3 significantly decreases the expression of male gamete markers on the transcriptome and proteome level but also affects regulators of translation. We further investigated the function of PfMD3-3xHA using in vivo using crosslinked RNA-Protein interaction capture followed by RNA-sequencing (CLIP-seq) to determine its RNA targets and IP-MS to determine protein interactors. We found 143 bound mRNA transcripts in early-stage gametocytes and 86 transcripts in late-stage gametocytes including arid/md4 andp230, not1-g, spm3 and morc mRNA bound at both stages. Interestingly, these CLIP targets decrease significantly in the ΔPfMD3 proteome, suggesting a role for PfMD3 in translational processing. IP-MS using a PfMD3-3xHA-tagged line further confirmed this role, showing an enrichment of proteins involved in mRNA metabolism. We then propose that PfMD3 functions as a Male Associated Regulator of Translation Initiation or Enhancement (MARTIE) in the human malaria parasite P. falciparum.

2024-09-01 | GSE267361 | GEO

The Plasmodium falciparum CCCH zinc finger protein MD3 regulates male gametocytogenesis through its interaction with RNA-binding proteins

Project description:Malaria transmission to mosquitoes is dependent on the formation of gametocytes. When fully matured, gametocytes are able to transform into gametes in the mosquito's midgut, a process accompanied with their egress from the enveloping erythrocyte. Gametocyte maturation and gametogenesis require a well-coordinated gene expression programme, involving a wide spectrum of regulatory proteins, ranging from histone modifiers to transcription factors to RNA-binding proteins. Here, we investigated the role of the CCCH-zinc finger protein MD3, in P. falciparum gametocytogenesis. MD3 was originally identified by us as an epigenetically regulated protein of immature gametocytes and recently shown to be involved in male development in a barcode-based screen in P. berghei. In P. falciparum, MD3 is mainly present in the cytoplasm of immature male gametocytes. Parasites deficient of MD3 are impaired in gametocyte maturation and male gametocyte exflagellation. BioID analysis in combination with co-immunoprecipitation assays unveiled an interaction network of MD3 with RNA-binding proteins like PABP1 and ALBA3, with translational initiators, regulators and repressors like elF4G, Puf1, NOT1 and CITH, and with other zinc finger proteins involved in gametocytogenesis, including ZNF4, MD1 and GD1. We conclude that MD3 is part of a regulator complex crucial for post-transcriptional fine-tuning of male gametocytogenesis.

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Next generation sequencing analysis of transcriptomes of Plasmodium falciparum male and female gametocytes

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