Journal Article

A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium

Billker, Oliver, Dickens, Nicholas J., Sinha, Abhinav, Graham, Anne L., Williams, April E., Waters, Andrew P., Modrzynska, Katarzyna K., Religa, Agnieszka A., Kafsack, Bjorn F. C., Berriman, Matthew, Hughes, Katie R., Pfander, Claudia, Cameron, Rachael, Bushell, Ellen, Otto, Thomas D., Llinás, Manuel

2014

Overview

Malaria parasites must produce gametocytes for transmission to the mosquito vector, although the molecular mechanisms underlying commitment to gametocyte production remain unclear; here this process is found to be controlled by PbAP2-G, a member of the ApiAP2 family of DNA-binding proteins, in the rodent-infecting Plasmodium berghei parasite. Malarial virulence factor primed for action For malaria parasites to be transmitted to the mosquito vector they must undergo sexual development and produce gametocytes. The molecular mechanisms underlying the commitment to gametocyte development have been unclear. Two complementary manuscripts now show that AP2-G, a member of the apicomplexan AP2 family of transcription factors, is a master regulator of sexual development in the malaria parasite, acting as a developmental switch by triggering the transcription of early gametocyte genes. Abhinav Sinha et al . worked with the rodent malaria parasite Plasmodium berghei , and Björn Kafsack et al . with the human pathogen P. falciparum . AP2-G activity in human infectious malaria parasites could be a potential target for antimalarials designed to interfere with gametocyte formation. Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus Plasmodium ) to be transmitted through mosquitoes 1 . The molecular mechanism(s) responsible for commitment have been hitherto unknown. Here we show that PbAP2-G, a conserved member of the apicomplexan AP2 (ApiAP2) family of DNA-binding proteins, is essential for the commitment of asexually replicating forms to sexual development in Plasmodium berghei , a malaria parasite of rodents. PbAP2-G was identified from mutations in its encoding gene, PBANKA_143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. Systematic gene deletion of conserved ApiAP2 genes in Plasmodium confirmed the role of PbAP2-G and revealed a second ApiAP2 member (PBANKA_103430, here termed PbAP2-G2) that significantly modulates but does not abolish gametocytogenesis, indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes. The data suggest a mechanism of commitment to gametocytogenesis in Plasmodium consistent with a positive feedback loop involving PbAP2-G that could be exploited to prevent the transmission of this pernicious parasite.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45 / 45/23 / 45/41 / 45/61 / 45/70 / 45/77 / 45/90 / 631/326/417/2549 / 64 / 82 / Animals / Chemical properties / Culicidae - parasitology / Deoxyribonucleic acid / DNA / DNA binding proteins / DNA sequencing / DNA-Binding Proteins - deficiency / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Epigenetics / Feedback, Physiological / Female / Flow cytometry / Gene expression / Gene Expression Regulation / Genomes / Germ Cells - cytology / Germ Cells - growth & development / Germ Cells - metabolism / Humanities and Social Sciences / letter / Malaria / Malaria - parasitology / Male / Methods / Mosquitoes / multidisciplinary / Mutation / Mutation - genetics / Nucleotide sequencing / Parasites / Physiological aspects / Plasmodium berghei - cytology / Plasmodium berghei - genetics / Plasmodium berghei - physiology / Plasmodium falciparum / Properties / Protein Transport / Proteins / Protozoan Proteins - genetics / Protozoan Proteins - metabolism / Reproduction, Asexual / Science / Sexual Development - genetics / Transcription factors / Transcription, Genetic / Vector-borne diseases