A NIMA-related protein kinase is essential for completion of the sexual cycle of malaria parasites.
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.
Reininger
Luc
L
INSERM U609, Wellcome Centre for Molecular Parasitology, University of Glasgow, Glasgow G11 6NU, Scotland, United Kingdom.
Billker
Oliver
O
Tewari
Rita
R
Mukhopadhyay
Arunima
A
Fennell
Clare
C
Dorin-Semblat
Dominique
D
Doerig
Caroline
C
Goldring
Dean
D
Harmse
Leonie
L
Ranford-Cartwright
Lisa
L
Packer
Jeremy
J
Doerig
Christian
C
D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D002453:Cell Cycle / Q000502:physiology*; D004261:DNA Replication / Q000502:physiology; D019143:Evolution, Molecular; D006801:Humans; D008018:Life Cycle Stages / Q000502:physiology*; D008540:Meiosis / Q000502:physiology; D008969:Molecular Sequence Data; D000072379:NIMA-Related Kinases; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D015800:Protozoan Proteins / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D016415:Sequence Alignment
D015800:Protozoan Proteins; D012333:RNA, Messenger; D011494:Protein Kinases; D000072379:NIMA-Related Kinases; C502081:NIMA-related kinase 4, Plasmodium falciparum; D017346:Protein Serine-Threonine Kinases