1. A NIMA-related protein kinase is essential for completion of the sexual cycle of malaria parasites
- Author
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Caroline Doerig, Rita Tewari, Leonie Harmse, Lisa C. Ranford-Cartwright, Luc Reininger, Arunima Mukhopadhyay, Christian Doerig, Clare Fennell, Dean Goldring, Oliver Billker, Jeremy Packer, and Dominique Dorin-Semblat
- Subjects
DNA Replication ,Molecular Sequence Data ,Plasmodium falciparum ,Protozoan Proteins ,Biology ,Protein Serine-Threonine Kinases ,Biochemistry ,Plasmodium ,Evolution, Molecular ,Meiosis ,Catalytic Domain ,parasitic diseases ,medicine ,Gametocyte ,Animals ,Humans ,NIMA-Related Kinases ,Amino Acid Sequence ,RNA, Messenger ,Molecular Biology ,Phylogeny ,Genetics ,Life Cycle Stages ,Zygote ,Cell Cycle ,Cell Biology ,Cell cycle ,medicine.disease ,biology.organism_classification ,Cell biology ,Protein Kinases ,Sequence Alignment ,Malaria - Abstract
The molecular mechanisms regulating the sexual development of malaria parasites from gametocytes to oocysts in their mosquito vector are still largely unexplored. In other eukaryotes, NIMA-related kinases (Neks) regulate cell cycle progression and have been implicated in the regulation of meiosis. Here, we demonstrate that Nek-4, a new Plasmodium member of the Nek family, is essential for completion of the sexual cycle of the parasite. Recombinant Plasmodium falciparum Nek-4 possesses protein kinase activity and displays substrate preferences similar to those of other Neks. Nek-4 is highly expressed in gametocytes, yet disruption of the nek-4 gene in the rodent malaria parasite P. berghei has no effect on gamete formation and subsequent fertilization. However, further differentiation of zygotes into ookinetes is abolished. Measurements of nuclear DNA content indicate that zygotes lacking Nek-4 fail to undergo the genome replication to the tetraploid level that precedes meiosis. Cell cycle progression in the zygote is identified as a likely precondition for its morphological transition to the ookinete and for the successful establishment of a malaria infection in the mosquito.