Abstract

Clonally variant protein expression in the malaria parasite Plasmodium falciparum 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 P. falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 is encoded by the multicopy var gene family and only a single variant is expressed in individual parasites, a concept known as mutual exclusion or singular gene choice. var gene activation occurs in situ and is achieved through the escape of one locus from epigenetic silencing. Singular gene choice is controlled at the level of transcription initiation and var 5′ upstream (ups) sequences harbour regulatory information essential for mutually exclusive transcription as well as for the trans-generational inheritance of the var activity profile. An additional level of control has recently been identified for the var2csa gene, where an mRNA element in the 5′ untranslated region (5′ UTR) is involved in the reversible inhibition of translation of var2csa transcripts. Here, we extend the knowledge on post-transcriptional var gene regulation to the common upsC type. We identified a 5′ UTR sequence that inhibits translation of upsC-derived mRNAs. Importantly, this 5′ UTR element efficiently inhibits translation even in the context of a heterologous upstream region. Further, we found var 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 P. falciparum.

Highlights

  • During intra-erythrocytic development, the human malaria parasite Plasmodium falciparum exports the major virulence factor erythrocyte membrane protein 1 (PfEMP1) to the red blood cell (RBC) surface [1]

  • The independent analysis of several truncated upsC sequences consistently showed that transcripts carrying a deletion of the 59 untranslated region (59 untranslated region (UTR)) MEE element gave rise to significantly higher hDHFR-GFP protein levels compared to transcripts carrying this region

  • Since hDHFR expression is subject to auto-regulation it is important to exclude the possibility that this mechanism may have been responsible for our observations

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Summary

Introduction

During intra-erythrocytic development, the human malaria parasite Plasmodium falciparum exports the major virulence factor erythrocyte membrane protein 1 (PfEMP1) to the red blood cell (RBC) surface [1]. Of the 60 var genes encoded in the haploid parasite genome, only a single variant is active at any given time [13] This singular var gene choice is regulated at the level of RNA polymerase II-mediated transcription initiation and results in mutually exclusive expression of PfEMP1 [14]. In contrast to silenced loci, the active var gene is associated with H3K9 acetylation and H3K4me2/3 as well as with the histone variants H2A.Z and H2B.Z in the ups region [26,32]. While in most of all cases daughter cells recapitulate the var transcription pattern of their progenitors due to epigenetic inheritance, occasional switching events result in antigenic variation of PfEMP1 [33,34]. In line with the essential roles of histone modifying enzymes in this process, recent studies observed the partial or complete breakdown of singular var gene choice in response to interfering with histone de-acetylation [30,35] or H3K36 methylation [36]

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