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Background The eukaryotic parasite  Plasmodium falciparum  causes millions of malarial infections annually while drug resistance to common anti-malarials is further confounding eradication efforts. Translation is an attractive therapeutic target that will benefit from a deeper mechanistic understanding. As the rate limiting step of translation, initiation is a primary driver of translational efficiency. It is a complex process regulated by both  cis  and  trans  acting factors, providing numerous potential targets. Relative to model organisms and humans,  P. falciparum  mRNAs feature unusual 5′ untranslated regions suggesting  cis -acting sequence complexity in this parasite may act to tune levels of protein synthesis through their effects on translational efficiency. Methods Here, in vitro translation is deployed to compare the role of  cis -acting regulatory sequences in  P. falciparum  and humans. Using parasite mRNAs with high or low translational efficiency, the presence, position, and termination status of upstream “AUG”s, in addition to the base composition of the 5′ untranslated regions, were characterized. Results The density of upstream “AUG”s differed significantly among the most and least efficiently translated genes in  P. falciparum , as did the average “GC” content of the 5′ untranslated regions. Using exemplars from highly translated and poorly translated mRNAs, multiple putative upstream elements were interrogated for impact on translational efficiency. Upstream “AUG”s were found to repress translation to varying degrees, depending on their position and context, while combinations of upstream “AUG”s had non-additive effects. The base composition of the 5′ untranslated regions also impacted translation, but to a lesser degree. Surprisingly, the effects of  cis -acting sequences were remarkably conserved between  P. falciparum  and humans. Conclusions While translational regulation is inherently complex, this work contributes toward a more comprehensive understanding of parasite and human translational regulation by examining the impact of discrete  cis- acting features, acting alone or in context.

Functional characterization of 5′ UTR cis-acting sequence elements that modulate translational efficiency in Plasmodium falciparum and humans