A <i>var</i> Gene Upstream Element Controls Protein Synthesis at the Level of Translation Initiation in <i>Plasmodium falciparum</i>

<div><p>Clonally variant protein expression in the malaria parasite <i>Plasmodium falciparum</i> generates phenotypic variability and allows isogenic populations to adapt to environmental changes encountered during blood stage infection. The underlying regulatory mechanisms are best studied for the major virulence factor <i>P. falciparum</i> erythrocyte membrane protein 1 (PfEMP1). PfEMP1 is encoded by the multicopy <i>var</i> gene family and only a single variant is expressed in individual parasites, a concept known as mutual exclusion or singular gene choice. <i>var</i> gene activation occurs <i>in situ</i> and is achieved through the escape of one locus from epigenetic silencing. Singular gene choice is controlled at the level of transcription initiation and <i>var</i> 5′ upstream (<i>ups)</i> sequences harbour regulatory information essential for mutually exclusive transcription as well as for the trans-generational inheritance of the <i>var</i> activity profile. An additional level of control has recently been identified for the <i>var2csa</i> gene, where an mRNA element in the 5′ untranslated region (5′ UTR) is involved in the reversible inhibition of translation of <i>var2csa</i> transcripts. Here, we extend the knowledge on post-transcriptional <i>var</i> gene regulation to the common <i>upsC</i> type. We identified a 5′ UTR sequence that inhibits translation of <i>upsC</i>-derived mRNAs. Importantly, this 5′ UTR element efficiently inhibits translation even in the context of a heterologous upstream region. Further, we found <i>var</i> 5′ UTRs to be significantly enriched in uAUGs which are known to impair the efficiency of protein translation in other eukaryotes. Our findings suggest that regulation at the post-transcriptional level is a common feature in the control of PfEMP1 expression in <i>P. falciparum</i>.</p>