Regulation of gene expression in Leishmania parasites: structure, function and post-transcriptional modification of RNA binding proteins

利什曼原虫寄生虫基因表达的调控：RNA结合蛋白的结构、功能和转录后修饰

• 批准号: 1949525
• 金额: --
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1949525
• 关键词: Regulation; gene; expression; Leishmania; parasites

The single-cell Leishmania parasite transforms into many different forms during its lifecycle to adapt to very different hosts; moving from mammals to sandflies and back to mammals via sandfly bites. Only Leishmania parasites of certain lifecycle stage forms can infect and survive in humans. Major changes to the Leishmania parasite's appearance, metabolism and virulence occur during these transitions that enable them to survive. Gene expression in Leishmania relies almost exclusively upon regulation of messenger RNAs. In response to changes in the environment, specific parasite proteins bind mRNAs and target them for protein production to guide and promote adaptation. Proteins that control the adaptation of these parasites enable them to survive in and infect humans. Such proteins are essential for the virulence and spread of the Leishmania parasite infection. The Leishmaniases are the second deadliest parasitic disease. Species of Leishmania threaten 350 million people worldwide on four continents. The World Health Organisation estimates 12 million people globally are currently infected and over 1 million new cases occur annually. No vaccine currently exists and available Leishmaniasis treatments are threatened by growing resistances and often overwhelmed by acute epidemics that are increasing in occurrence and severity. New treatments and vaccines are desperately needed and the UK government is committed to the World Health Organisation's recent call to further support Neglected Tropical Disease research. We have isolated specific RNA binding trans-regulatory proteins that are modified and regulated through arginine methylation. We have shown that levels of the methyltransferase enzyme responsible for this modification modulate Leishmania major infectivity and virulence. The project will focus on how arginine methylation modifies the 3D structure, interaction profile and function of target RNA binding proteins, and how this post-translational modification affects parasite infectivity and virulence. A molecular-level understanding of this epigenetic process will greatly advance our knowledge of post-transcriptional trans-regulation in Leishmania parasites.

单细胞利什曼原虫在其生命周期中转变为许多不同的形式，以适应不同的宿主;从哺乳动物到白蛉，再通过白蛉叮咬回到哺乳动物。只有某些生命周期阶段形式的利什曼原虫才能感染人类并在人类中存活。利什曼原虫的外观，代谢和毒力的主要变化发生在这些转变，使他们能够生存。利什曼原虫的基因表达几乎完全依赖于信使RNA的调节。为了应对环境的变化，特定的寄生虫蛋白质结合mRNA并靶向它们产生蛋白质，以指导和促进适应。控制这些寄生虫适应的蛋白质使它们能够在人体内生存并感染人类。这些蛋白质是利什曼原虫感染的毒力和传播所必需的。利什曼病是第二种最致命的寄生虫病。利什曼原虫威胁着全球四大洲3.5亿人的生命。世界卫生组织估计，目前全球有1200万人感染，每年有100多万新病例。目前没有疫苗，可用的利什曼病治疗受到日益增长的耐药性的威胁，并且经常被发生率和严重程度不断增加的急性流行病所淹没。迫切需要新的治疗方法和疫苗，英国政府致力于响应世界卫生组织最近的呼吁，进一步支持被忽视的热带病研究。我们已经分离出特异性RNA结合的反式调节蛋白，其通过精氨酸甲基化进行修饰和调节。我们已经表明，甲基转移酶的水平负责这种修改调节利什曼原虫主要的感染性和毒力。该项目将重点关注精氨酸甲基化如何改变靶RNA结合蛋白的3D结构、相互作用谱和功能，以及这种翻译后修饰如何影响寄生虫的感染性和毒力。对这一表观遗传过程的分子水平理解将极大地推进我们对利什曼原虫寄生虫转录后反式调节的了解。