An Essential Role for the Plasmodium Nek-2 Nima-related Protein Kinase in the Sexual Development of Malaria Parasites

Abstract

The molecular control of cell division and development in malaria parasites is far from understood. We previously showed that a Plasmodium gametocyte-specific NIMA-related protein kinase, nek-4, is required for completion of meiosis in the ookinete, the motile form that develops from the zygote in the mosquito vector. Here, we show that another NIMA-related kinase, Pfnek-2, is also predominantly expressed in gametocytes, and that Pfnek-2 is an active enzyme displaying an in vitro substrate preference distinct from that of Pfnek-4. A functional nek-2 gene is required for transmission of both Plasmodium falciparum and the rodent malaria parasite Plasmodium berghei to the mosquito vector, which is explained by the observation that disruption of the nek-2 gene in P. berghei causes dysregulation of DNA replication during meiosis and blocks ookinete development. This has implications (i) in our understanding of sexual development of malaria parasites and (ii) in the context of control strategies aimed at interfering with malaria transmission.

The kinomes of apicomplexan parasites

“…Pfnek-2 (PFE1290w) and Pfnek-3 (PFL0080c) are restricted to haemosporidians. Pfnek-2 is essential for transmission to the mosquito, and studies with the P. berghei orthologues identified a defect in meiosis in parasites lacking the enzyme, as was the case for Pbnek-4 [86,87]. Pfnek-3 has been reported to activate Pfmap-2 in vitro, like Pfnek-1 [88].…”

Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum

“…If a specific kinase regulates commitment to gametocytogenesis but is also required for (an)other function(s) essential for asexual growth, uncovering the former will require conditional expression or activity of the 36 kinases that are classed in this study as 'likely essential' . Some of the ePKs that are not essential for asexual growth have already been demonstrated to be required for successful infection of the mosquito vector 32,36 ; in light of this we are currently aiming to phenotype KO clones of all non-essential ePKs in the mosquito.…”

The development of malaria parasites in the mosquito midgut

“…berghei resulted in male sterility and blocked fertilization (Hirai et al ., 2008; Liu et al ., 2008). Following gamete fusion, nuclear fusion ensues, and over the next 3 h, meiosis occurs, and the zygote becomes tetraploid (Janse et al ., 1986), a process involving the NIMA‐related kinases Nek‐2 and Nek‐4 (Reininger et al ., 2005, 2009). Parasite tetraploidy persists throughout the ookinete stage until sporozoite budding in the oocyst restores the haploid state (Janse et al ., 1986) (Table 1).…”