PfMD3 protein controls translation in malaria male gametes

A study in Nature Communications characterizes PfMD3, a CCCH-type zinc-finger protein of the malaria parasite Plasmodium falciparum, and links it to the fertility of male gametes. Genetic disruption of PfMD3 produced a male fertility defect and decreased infectivity to mosquitoes, the authors report doi.org. Malaria claims over half a million lives each year, and gametocytes are the only parasite form infectious to female Anopheles mosquitoes during a blood meal doi.org.

In each 48-hour cycle of red blood cell invasion and rupture, a subset of blood-stage parasites converts to gametocytes. The parasite genome encodes few DNA-binding proteins but hundreds of predicted RNA-binding proteins, which points to regulation after transcription and at the level of translation doi.org. It also encodes about 170 zinc-finger proteins; in higher eukaryotes, the CCCH type is involved in mRNA splicing, polyadenylation, decay and promotion of translation doi.org.

PfMD3 and male gametocyte development

PfMD3 is a 485-amino-acid protein. It has a CCCH-type zinc-finger domain (residues 163–185) and a predicted lysine-proline-rich ribosome-binding receptor domain (residues 260–295), found only in species of the subgenus Laverania. Two nucleolar localization signals are also predicted doi.org.

The authors found that PfMD3 is preferentially expressed in male gametocytes. In the knockout line, mosquito transmission fell markedly and the number of P230p-positive male gametocytes was reduced doi.org. Transcriptome and proteome analysis showed a significant decrease in male-associated transcripts and proteins, and single-cell RNA sequencing showed a smaller male lineage among gametocytes lacking PfMD3 doi.org.

RNA binding and translation

PfMD3 binds directly to a specific sequence motif in mRNAs that are necessary for male gamete development doi.org. Gametocyte proteins encoded by these bound transcripts decrease significantly in PfMD3 knockout parasites, which the authors interpret as an effect on translation doi.org.

PfMD3 also interacts with proteins involved in ribonucleoprotein biogenesis, mRNA processing and nuclear export, as well as components of the translational machinery doi.org. Based on an integrated analysis of these datasets, the authors conclude that PfMD3 is an RNA-binding protein that affects lineage-specific translation and male gamete fertility doi.org.

Plasmodium falciparum PfMD3 protein regulates translation; knockout lowers mosquito infectivity

PfMD3 and male gametocyte development

RNA binding and translation

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