Extra-translational roles of aminoacyl tRNA synthetases in connection to disease

氨酰 tRNA 合成酶与疾病相关的翻译外作用

• 批准号: 8326643
• 负责人: Xiang-Lei Yang
• 金额: $ 35.72万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-06 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8326643
• 关键词: Amino Acyl-tRNA Synthetases; Aminoacylation; Amyotrophic Lateral Sclerosis; Apoptosis; Binding; C-terminal; Catalysis; Cells; Charcot-Marie-Tooth Disease; Cytoplasmic Tail; Death Domain; Disease; Enzyme Activation; Enzymes; Family; Frequencies; Genes; Glycine; Glycine-Specific tRNA; Glycine-tRNA Ligase; Goals; Hereditary Motor and Sensory Neuropathies; Homeostasis; Human; Individual; Knowledge; Ligation; Light; Mediating; Modification; Mutation; Neurons; Parkinson Disease; Pathway interactions; Peripheral Nervous System Diseases; Phenotype; Physical condensation; Population; Protein Biosynthesis; Proteins; Reaction; Role; Signal Transduction; Testing; Transfer RNA; Tumor Necrosis Factor Receptor; Tyrosine-tRNA Ligase; Ubiquitin; Ubiquitin Like Proteins; Work; YARS gene; abstracting; hereditary neuropathy; human disease; member; nervous system disorder; public health relevance

DESCRIPTION (provided by applicant): Extra-translational role of aminoacyl-tRNA synthetases in connection to disease Abstract: My goal is to understand the expanded functions of glycyl-tRNA synthetase (GlyRS) and how they connect with Charcot-Marie-Tooth (CMT) diseases. GlyRS is one of 20 members of the aminoacyl-tRNA synthetase (AARS) family that catalyzes aminoacylation of transfer tRNAin the first step of protein synthesis. Dominant mutations of GARS (gene for GlyRS) and YARS (gene for tyrosyl-tRNA synthetase) have been identified in the human population to cause Charcot-Marie-Tooth (CMT) diseases. Also known as hereditary motor and sensory neuropathies, CMT diseases are the most common heritable peripheral neuropathy, occurring with a frequency of approximately 1 in 2500 individuals. The CMT phenotype does not arise from a reduction in the essential aminoacylation function. This observation led to our hypothesis that these two tRNA synthetases have expanded functions (beyond aminoacylation) that are critical to understanding their connection to CMT. The focus of the proposal is on GlyRS. A search for interaction partners of GlyRS identified Daxx, a protein that interacts with the cytoplasmic domain of Fas. Fas is a member of the tumor necrosis factor receptor superfamily, and the Fas-Daxx interaction enhances Fas-mediated apoptosis. Significantly, The Fas-Daxx pathway is implicated in CMT, as well as in many other neurological disorders including Amyotrophic Lateral Sclerosis and Parkinson's disease. These considerations raised the possibility that the interaction between GlyRS and Daxx is relevant to the CMT disease-causing mechanism. Surprisingly, we found that a modified form of GlyRS specifically interacts with Daxx. We have identified the modifier of GlyRS to be a ubiquitin-like protein called NEDD8. NEDDylation is known to regulate the function of its substrates. Interestingly, the residue on NEDD8 for conjugation to substrate is the C-terminal glycine, which is conserved in ubiquitin and in almost all ubiquitin-like proteins. The first reaction in NEDDylation is the adenylation of the C- terminal glycine by condensation with ATP. It is chemically the same reaction as the first step of catalysis by GlyRS in aminoacylation. This consideration led us to propose that GlyRS is involved in the NEDDylation of Daxx which, in turn, regulates Daxx-mediated apoptosis. Indeed, we found that GlyRS-associated Daxx is NEDDylated. Thus, the work proposed here will advance understanding of the extra-translational roles of AARS and their possible connection to human disease. PUBLIC HEALTH RELEVANCE: Narrative This project will aid in understanding how tRNA synthetases function in connection to Charcot-Marie-Tooth disease, which is the most common hereditary neuropathy. The knowledge we gain in this study will also shed light on other neurological diseases such as Amyotrophic Lateral Sclerosis (Lou Gehrig's disease) and Parkinson's disease.

描述（由申请人提供）：氨酰 tRNA 合成酶与疾病相关的翻译外作用 摘要：我的目标是了解甘氨酰 tRNA 合成酶 (GlyRS) 的扩展功能以及它们如何与 Charcot-Marie-Tooth (CMT) 连接）疾病。 GlyRS 是氨酰-tRNA 合成酶 (AARS) 家族的 20 个成员之一，可在蛋白质合成的第一步中催化转移 tRNA 的氨酰化。已在人群中发现 GARS（GlyRS 基因）和 YARS（酪氨酰-tRNA 合成酶基因）的显性突变可导致腓骨肌萎缩症 (CMT) 疾病。 CMT 疾病也称为遗传性运动和感觉神经病，是最常见的遗传性周围神经病，发生频率约为 2500 人中有 1 人。 CMT 表型并非由必需氨酰化功能的降低引起。这一观察结果导致我们假设这两种 tRNA 合成酶具有扩展的功能（超出氨酰化作用），这对于理解它们与 CMT 的联系至关重要。该提案的重点是 GlyRS。对 GlyRS 相互作用伙伴的搜索发现了 Daxx，一种与 Fas 细胞质结构域相互作用的蛋白质。 Fas 是肿瘤坏死因子受体超家族的成员，Fas-Daxx 相互作用可增强 Fas 介导的细胞凋亡。值得注意的是，Fas-Daxx 通路与 CMT 以及许多其他神经系统疾病（包括肌萎缩侧索硬化症和帕金森病）有关。这些考虑提出了 GlyRS 和 Daxx 之间的相互作用与 CMT 致病机制相关的可能性。令人惊讶的是，我们发现 GlyRS 的修饰形式与 Daxx 特异性相互作用。我们已经鉴定出 GlyRS 的修饰物是一种名为 NEDD8 的类泛素蛋白。众所周知，NEDDylation 可以调节其底物的功能。有趣的是，NEDD8 上用于与底物缀合的残基是 C 端甘氨酸，它在泛素和几乎所有泛素样蛋白中都是保守的。 NEDDylation 中的第一个反应是通过与 ATP 缩合对 C 末端甘氨酸进行腺苷酸化。它在化学上与氨酰化中GlyRS催化的第一步相同。这种考虑使我们提出 GlyRS 参与 Daxx 的 NEDDylation，进而调节 Daxx 介导的细胞凋亡。事实上，我们发现 GlyRS 相关的 Daxx 是 NEDDylated。因此，这里提出的工作将促进对 AARS 的翻译外作用及其与人类疾病的可能联系的理解。 公共健康相关性：叙述 该项目将有助于了解 tRNA 合成酶如何与腓骨肌萎缩症（一种最常见的遗传性神经病）相关。我们在这项研究中获得的知识还将揭示其他神经系统疾病，例如肌萎缩侧索硬化症（卢伽雷氏病）和帕金森氏病。