PfeIK1, a eukaryotic initiation factor 2 kinase of the human malaria parasite Plasmodium falciparum, regulates stress-response to amino-acid starvation

Clare Fennell, Shalon Babbitt, Ilaria Russo, Jonathan Wilkes, Lisa Ranford-Cartwright, Daniel E. Goldberg, Christian Doerig

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Abstract

Background. Post-transcriptional control of gene expression is suspected to play an important role in malaria parasites. In yeast and metazoans, part of the stress response is mediated through phosphorylation of eukaryotic translation initiation factor 2 (eIF2), which results in the selective translation of mRNAs encoding stress-response proteins. Methods. The impact of starvation on the phosphorylation state of PfeIF2 was examined. Bioinformatic methods were used to identify plasmodial eIF2 kinases. The activity of one of these, PfeIK1, was investigated using recombinant protein with non-physiological substrates and recombinant PfeIF2. Reverse genetic techniques were used to disrupt the pfeik1 gene. Results. The data demonstrate that the Plasmodium falciparum eIF2 orthologue is phosphorylated in response to starvation, and provide bioinformatic evidence for the presence of three eIF2 kinases in P. falciparum, only one of which (PfPK4) had been described previously. Evidence is provided that one of the novel eIF2 kinases, PfeIK1, is able to phosphorylate the P. falciparum eIF2 orthologue in vitro. PfeIK1 is not required for asexual or sexual development of the parasite, as shown by the ability of pfeik1 -parasites to develop into sporozoites. However, eIF2 phosphorylation in response to starvation is abolished in pfeik1-asexual parasites. Conclusion. This study strongly suggests that a mechanism for versatile regulation of translation by several kinases with a similar catalytic domain but distinct regulatory domains, is conserved in P. falciparum.

Original languageEnglish
Article number99
JournalMalaria Journal
Volume8
Issue number1
DOIs
StatePublished - Jun 4 2009

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