Impact of telomere-associated protein complexes on VSG expression site regulation and structure in Trypanosoma brucei

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The protist pathogen, Trypanosoma brucei, is the causative agent of fatal diseases such as sleeping sickness in humans and nagana in livestock in sub-Saharan Africa. During their life cycle, trypanosomes have to shuttle between a mammalian host and the tsetse fly vector. In the mammalian host, immune evasion of T. brucei bloodstream form cells (BSF) relies on antigenic variation, which includes monoallelic expression and periodic switching of variant surface glycoprotein (VSG) genes. The active VSG is always transcribed from one of only 15 subtelomeric expression sites (ESs) and telomere-associated proteins have been shown to regulate expression and recombination events at these sites. During differentiation from BSF to the insect-resident procyclic form (PCF), the active ES is transcriptionally silenced. The exact molecular mechanisms that regulate antigenic variation are still elusive because only a few telomere-associated proteins have been identified and characterized so far.We used quantitative interactomics to determine the composition of telomere protein complexes in T. brucei and identified 17 telomere-associated proteins including already validated telomeric proteins. In this grant proposal, we suggest two independent but complementary projects to characterise novel telomere-associated proteins and elucidate their putative function in antigenic variation and telomere maintenance. Preliminary data already suggest different telomere complex compositions in the two forms of the parasite. To validate our quantitative interactomics approach, we could already show that one of the novel telomere-binding proteins, TelAP1, forms a complex with telomeric proteins TRF, RAP1 and TIF2 and influences ES silencing kinetics during developmental differentiation.