Abstract
During their complex life cycles, the Apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii employ several layers of regulation of their gene expression. One such layer is mediated at the level of translation through upstream open reading frames (uORFs). As uORFs are found in the upstream regions of a majority of transcripts in both the parasites, it is essential that their roles in translational regulation be appreciated to a greater extent. This review provides a comprehensive summary of studies that show uORF-mediated gene regulation in these parasites and highlights examples of clinically and physiologically relevant genes, including var2csa in P. falciparum, and ApiAT1 in T. gondii, that exhibit uORF-mediated regulation. In addition to these examples, several studies that use bioinformatics, transcriptomics, proteomics and ribosome profiling also indicate the possibility of widespread translational regulation by uORFs. Further analysis of these genome-wide datasets, taking into account uORFs associated with each gene, will reveal novel genes involved in key biological pathways such as cell-cycle progression, stress-response and pathogenicity. The cumulative evidence from studies presented in this review suggests that uORFs will play crucial roles in regulating gene expression during clinical disease caused by these important human pathogens.
Highlights
Eukaryotic translation initiation is a tightly regulated, multi-step process that involves scanning of messenger RNA by the preinitiation complex (Kozak, 1980)
Similar to uAUGs, upstream open reading frames, defined as an upstream start codon followed by an in-frame stop codon, engage the scanning ribosome with varying capacities, which in turn alters the level of the protein encoded by the main coding sequence (CDS)
As the asexual stages of P. falciparum are the cause of the clinical symptoms of malaria, a better understanding of upstream open reading frames (uORFs)-mediated translational regulation may lead to the identification of new targets for therapeutic interventions
Summary
Eukaryotic translation initiation is a tightly regulated, multi-step process that involves scanning of messenger RNA (mRNA) by the preinitiation complex (Kozak, 1980). The phosphorylation of eIF2α, which is carried out by members of the eIF2α kinase family (Pakos-Zebrucka et al, 2016; Wek, 2018; Costa-Mattioli and Walter, 2020), leads to global inhibition of protein synthesis and preferential translation of transcripts encoding proteins involved in mediating the adaptive response These studies indicate that the phosphorylation status of eIF2α is a global indicator for translational regulation of large numbers of genes, some of which could be controlled by uORFs. A more definitive role for uORFs in translational regulation is provided by the presence of ribosomal footprints on the 5′ leader of the transcripts undergoing PTGR (Schneider-Poetsch et al, 2010; Garreau de Loubresse et al, 2014). The current status of the field will be summarized and the need to further understand the phenomenon of uORF-mediated PTGR in apicomplexan parasites will be highlighted in detail
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