Abstract
Variegated surface antigen expression is key to chronic infection and pathogenesis of the human malaria parasite Plasmodium falciparum. This protozoan parasite expresses distinct surface molecules that are encoded by clonally variant gene families such as var, rif and stevor. The molecular mechanisms governing activation of individual members remain ill-defined. To investigate the molecular events of the initial transcriptional activation process we focused on a member of the apicomplexan ApiAP2 transcription factor family predicted to bind to the 5′ upstream regions of the var gene family, AP2-exp (PF3D7_1466400). Viable AP2-exp mutant parasites rely on expressing no less than a short truncated protein including the N-terminal AP2 DNA-binding domain. RNA-seq analysis in mutant parasites revealed transcriptional changes in a subset of exported proteins encoded by clonally variant gene families. Upregulation of RIFINs and STEVORs was validated at the protein levels. In addition, morphological alterations were observed on the surface of the host cells infected by the mutants. This work points to a complex regulatory network of clonally variant gene families in which transcription of a subset of members is regulated by the same transcription factor. In addition, we highlight the importance of the non-DNA binding AP2 domain in functional gene regulation.
Highlights
Worldwide, 3.3 billion people are at risk of malaria, which in 2013 afflicted 198 million people, causing 584,000 deaths[1]
To shed light into the molecular process that initiates activation of clonally variant gene families in heterochromatin regions, we decided to investigate the role of an ApiAP2 member termed here AP2-exp (PF3D7_1466400) that was predicted to bind to promoter regions of var genes[19]
Since predicted binding sites for AP2-exp are enriched in upstream regions of var genes, we investigated transcript levels of the var gene family by quantitative real-time PCR, on cDNA prepared from 14 hours post-invasion ring stages
Summary
3.3 billion people are at risk of malaria, which in 2013 afflicted 198 million people, causing 584,000 deaths[1]. P. falciparum expresses other multigene virulence antigens that are exported to the surface of the red blood cell, the RIFINs, STEVORs, PfMC-2TMs (P. falciparum Maurer’s clefts-two transmembrane) and SURFINS, which are clonally variant[5,6] Growing evidence suggests these proteins play roles in key biological processes as diverse as invasion, rosetting, membrane rigidity and trafficking[6,7,8,9,10,11,12]. We sought to define the role of AP2-exp in virulence genes regulation in P. falciparum The orthologue of this protein in the murine malaria parasite P. berghei, AP2-Sp, has been shown to be expressed exclusively in the sporozoite stage[24] but recently, in a knockout screen of P. berghei AP2s, the authors observed a slight phenotype in blood stages, accompanied by transcriptional deregulation of 265 genes[30]. Our work suggests that the non-DNA-binding AP2-exp region is a critical factor that contributes to the regulation of a subset of virulence genes in P. falciparum
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