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

端粒相关蛋白复合物对布氏锥虫 VSG 表达位点调控和结构的影响

• 批准号: 404419679
• 负责人: Dr. Falk Butter
• 金额: --
• 依托单位: Institut für molekulare Virologie und Zellbiologie (IMVZ)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/404419679?language=en
• 关键词: Impact; telomere; associated; protein; complexes

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.

原生生物病原体布氏锥虫是致命疾病的病原体，如人类昏睡病和撒哈拉以南非洲牲畜长角线虫病。在其生命周期中，锥虫必须在哺乳动物宿主和采采蝇载体之间穿梭。在哺乳动物宿主中，T.布鲁氏菌血流形成细胞（BSF）依赖于抗原变异，其包括单等位基因表达和变异表面糖蛋白（VSG）基因的周期性转换。活性VSG总是从仅有的15个亚端粒表达位点（ES）之一转录，并且端粒相关蛋白已被证明调节这些位点的表达和重组事件。在从BSF到昆虫驻留的原环形式（PCF）的分化过程中，活性ES被转录沉默。由于迄今为止只鉴定和表征了少数端粒相关蛋白，因此调控抗原变异的确切分子机制仍然是难以捉摸的。brucei，并鉴定了17种端粒相关蛋白，包括已经验证的端粒蛋白。在这项资助计划中，我们提出了两个独立但互补的项目来研究新的端粒相关蛋白，并阐明它们在抗原变异和端粒维持中的假定功能。初步数据已经表明，在这两种形式的寄生虫不同的端粒复合体组成。为了验证我们的定量相互作用组学方法，我们已经可以表明，一种新的端粒结合蛋白，TelAP 1，形成一个复杂的端粒蛋白TRF，RAP 1和TIF 2，并影响ES沉默动力学在发育分化。