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Translational regulation in blood stages of the malaria parasite Plasmodium spp.: systems‐wide studies pave the way

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The malaria parasite Plasmodium spp. varies the expression profile of its genes depending on the host it resides in and its developmental stage. Virtually all messenger RNA (mRNA) is expressed in a monocistronic manner, with transcriptional activation regulated at the epigenetic level and by specialized transcription factors. Furthermore, recent systems‐wide studies have identified distinct mechanisms of post‐transcriptional and translational control at various points of the parasite lifecycle. Taken together, it is evident that ‘just‐in‐time’ transcription and translation strategies coexist and coordinate protein expression during Plasmodium development, some of which we review here. In particular, we discuss global and specific mechanisms that control protein translation in blood stages of the human malaria parasite Plasmodium falciparum, once a cytoplasmic mRNA has been generated, and its crosstalk with mRNA decay and storage. We also focus on the widespread translational delay observed during the 48‐hour blood stage lifecycle of P. falciparum—for over 30% of transcribed genes, including virulence factors required to invade erythrocytes—and its regulation by cis‐elements in the mRNA, RNA‐processing enzymes and RNA‐binding proteins; the first‐characterized amongst these are the DNA‐ and RNA‐binding Alba proteins. More generally, we conclude that translational regulation is an emerging research field in malaria parasites and propose that its elucidation will not only shed light on the complex developmental program of this parasite, but may also reveal mechanisms contributing to drug resistance and define new targets for malaria intervention strategies. WIREs RNA 2016, 7:772–792. doi: 10.1002/wrna.1365 This article is categorized under: Translation > Translation Regulation
Lifecycle of Plasmodium spp. parasites in the mammalian host and mosquito vector. The timing of different stages of P. falciparum in the human host is indicated. Instances of translational regulation and mRNA decay are also indicated. Note that the monkey malaria parasite P. knowlesi has recently been identified to infect humans.
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Molecular basis of translational regulation in malaria parasites. Translational regulation in the cytoplasm can occur during the initiation, elongation, and termination phases. This can be co‐regulated by factors that mediate decay and repression. eIF, eukaryotic Initiation Factor; tRNAmet, tRNA charged with methionine; eEF, eukaryotic Elongation Factor; eRF, eukaryotic Release Factor; eIF4F complex, eIF4E + eIF4G + eIF4A; PABP, Poly(A)‐Binding Protein; UTR, Untranslated Region; CDS, Coding Sequence; uORF, upstream Open Reading Frame; PBE, Puf‐Binding Element.
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Stages of mRNA maturation and cytoplasmic outcomes. Once a pre‐mRNA is transcribed in the nucleus from a given GOI (gene of interest), it is co‐ and post‐transcriptionally processed by splicing, 5′ cap modification, and 3′ polyadenylation to yield a mature mRNA. For select GOIs in Plasmodium falciparum, so‐called cryptic RNAs and antisense RNAs have been described in asexual blood stages, which may regulate transcription and/or translation. The mature mRNA is then bound by nuclear ribonucleoprotein (RNP) complexes and transported to the cytoplasm where it faces three outcomes: (1) Translation, mediated by the 80S ribosome to synthesize a polypeptide chain; (2) Decay, mediated by ribonucleases; and (3), Repression, which may occur in the context of mRNA‐RNP (mRNP) granules composed of different classes of proteins such as RNA helicases, RNA‐binding proteins, and translation‐associated factors.
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