Reininger Luc, Billker Oliver, Tewari Rita, Mukhopadhyay Arunima, Fennell Clare, Dorin-Semblat Dominique, Doerig Caroline, Goldring Dean, Harmse Leonie, Ranford-Cartwright Lisa, Packer Jeremy, Doerig Christian
INSERM U609, Wellcome Centre for Molecular Parasitology, University of Glasgow, Glasgow G11 6NU, Scotland, United Kingdom.
J Biol Chem. 2005 Sep 9;280(36):31957-64. doi: 10.1074/jbc.M504523200. Epub 2005 Jun 21.
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.
疟原虫在其蚊媒中从配子体发育成卵囊这一有性发育过程的分子机制，目前在很大程度上仍未得到充分探索。在其他真核生物中，NIMA相关激酶（Neks）调节细胞周期进程，并与减数分裂的调控有关。在此，我们证明Nek-4是Nek家族中疟原虫的一个新成员，对疟原虫有性周期的完成至关重要。重组恶性疟原虫Nek-4具有蛋白激酶活性，并且表现出与其他Neks相似的底物偏好。Nek-4在配子体中高度表达，然而，啮齿动物疟原虫伯氏疟原虫中nek-4基因的破坏对配子形成和随后的受精没有影响。但是，合子进一步分化为动合子的过程被阻断。核DNA含量的测量表明，缺乏Nek-4的合子无法进行基因组复制达到减数分裂前的四倍体水平。合子中的细胞周期进程被确定为其向动合子形态转变以及在蚊子中成功建立疟疾感染的一个可能前提条件。
