Identification of acis‐actingDNA–protein interaction implicated in singularvargene choice inPlasmodium falciparum

Nicolas M. B. Brancucci,Christian Flueck,Christoph D. Schmid,Kathrin Witmer,Till S. Voss

doi:10.1111/cmi.12004

Nicolas M. B. Brancucci, Christian Flueck + Show 3 more

Open Access

https://doi.org/10.1111/cmi.12004

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Abstract

Plasmodium falciparum is responsible for the most severe form of malaria in humans. Antigenic variation of P. falciparum erythrocyte membrane protein 1 leads to immune evasion and occurs through switches in mutually exclusive var gene transcription. The recent progress in Plasmodium epigenetics notwithstanding, the mechanisms by which singularity of var activation is achieved are unknown. Here, we employed a functional approach to dissect the role of var gene upstream regions in mutually exclusive activation. Besides identifying sequence elements involved in activation and initiation of transcription, we mapped a region downstream of the transcriptional start site that is required to maintain singular var gene choice. Activation of promoters lacking this sequence occurs no longer in competition with endogenous var genes. Within this region we pinpointed a sequence-specific DNA–protein interaction involving a cis-acting sequence motif that is conserved in the majority of var loci. These results suggest an important role for this interaction in mutually exclusive locus recognition. Our findings are furthermore consistent with a novel mechanism for the control of singular gene choice in eukaryotes. In addition to their importance in P. falciparum antigenic variation, our results may also help to explain similar processes in other systems.

Highlights

Many unicellular pathogens use antigenic variation to escape adaptive immune responses in the host
Antigenic variation of P. falciparum erythrocyte membrane protein 1 leads to immune evasion and occurs through switches in mutually exclusive var gene transcription
We employed a functional approach to dissect the role of var gene upstream regions in mutually exclusive activation

Summary

Introduction

Many unicellular pathogens use antigenic variation to escape adaptive immune responses in the host. While the underlying control pathways are highly diverse in different systems, both mechanistically and in terms of complexity, antigenic variation is defined by two basic concepts. The antigens are encoded by gene families, the members of which are expressed in a mutually exclusive manner. Switches in the expression of individual members lead to antigenic variation of surface-exposed antigens. In several medically important pathogens such as Borrelia spp., Neisseria spp., Giardia lamblia, Plasmodium falciparum and Trypanosoma brucei, this paradigm of clonal phenotypic variation reaches a remarkable yet poorly understood level of sophistication (Deitsch et al, 2009; Dzikowski and Deitsch, 2009; Morrison et al, 2009; Prucca and Lujan, 2009)

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