Uncovering non-autonomous mechanisms of control over translational attenuation during heat shock in the metazoan C. elegans

揭示后生动物秀丽隐杆线虫热休克过程中控制平移衰减的非自主机制

基本信息

批准号：
9167368
负责人：
Veena Prahlad
金额：
$ 18.73万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9167368
关键词：
Ablation Animal Model Attenuated Caenorhabditis elegans Cells Cellular Stress Response Chaperone Gene Control Animal Coupled Data Development Diagnosis EIF-2alpha Endoplasmic Reticulum Environment Eukaryotic Initiation Factors Gene Expression Genes Genetic Transcription HSF1 Heat Stress Disorders Heat shock proteins Heat-Shock Response Knowledge Metabolic Diseases Molecular Chaperones Nervous system structure Neurodegenerative Disorders Neurons Organism Pathway interactions Peptide Initiation Factors Phase Phosphorylation Phosphotransferases Polyribosomes Process Protein Biosynthesis Protein Kinase Proteins Repression Role Serotonergic System Serotonin Signal Pathway Signal Transduction Stress Testing Tissues Translation Initiation Translations Up-Regulation Work attenuation biological adaptation to stress body system cell type environmental stressor gene induction intercellular communication meetings neurotransmission optogenetics programs receptor response

项目摘要

The initiation of translation is an important point of control in the response of cells to environmental stress. Stress conditions activate stress-responsive kinases that inhibit translation initiation by phosphorylating the alpha subunit of the eukaryotic initiation factor 2 (eIF2α) which results in polysome disassembly and subsequent attenuation of translation. In addition to attenuating translation, stressful environments also activate the transcription of protective molecular chaperones or heat shock proteins (HSPs). One of the major recent developments in the understanding of stress responses is the discovery that the transcriptional expression of chaperones during stress is not triggered autonomously by cells undergoing macromolecular damage, but is instead cell non-autonomously orchestrated by the nervous system. However, it is not known whether translational attenuation across the different cells of a metazoan is also coordinated through similar cell-cell signaling pathways that modulate transcription. In ongoing studies, we have found that although transcription of chaperones and translational attenuation occur independent of each other upon heat shock, as with the transcriptional upregulation of chaperone gene expression, the phosphorylation of eIF2α upon heat stress in C. elegans is dependent on the serotonergic system. These data suggest that serotonergic control over eIF2α phosphorylation may act to integrate transcriptional and translational responses to stress across cells of an organism. This is the hypothesis we aim to test in this proposal. Specifically, we will test (1) how translation attenuation is coupled to neuronal serotonin release and (2) whether translation attenuation is coordinated with HSP upregulation through neuronal 5-HT release. We anticipate that these studies will fill a critical gap in knowledge regarding the coordination of translational upon stress between tissues of a metazoan. These studies will therefore be important for understanding how stress contributes to the progression of metabolic and neurodegenerative diseases and allow the development of new strategies for diagnosis and treatment.

翻译的起始是细胞对环境应激反应的重要控制点。应激条件激活应激反应激酶，通过磷酸化抑制翻译起始真核起始因子 2 (eIF2α) 的 α 亚基，导致多核糖体解体和随后的翻译减弱除了翻译减弱之外，压力环境也会减弱。激活保护性分子伴侣或热休克蛋白 (HSP) 的转录。在理解应激反应方面的最新重大进展是发现应激期间伴侣蛋白的转录表达不是由经历应激的细胞自主触发的大分子损伤，而是由神经系统非自主地精心策划的细胞损伤。然而，尚不清楚后生动物不同细胞之间的翻译衰减是否还通过调节转录的类似细胞间信号传导途径进行协调。正在进行的研究中，我们发现虽然分子伴侣的转录和翻译衰减热休克时彼此独立地发生，就像分子伴侣的转录上调一样基因表达，秀丽隐杆线虫热应激时 eIF2α 的磷酸化取决于这些数据表明，血清素能控制 eIF2α 磷酸化可能起作用。整合生物体细胞间对应激的转录和翻译反应。我们旨在在本提案中测试的假设具体而言，我们将测试（1）平移衰减如何。与神经元血清素释放耦合以及（2）翻译衰减是否与 HSP 协调我们预计这些研究将填补神经 5-HT 释放的关键空白。关于后生动物组织之间的应激翻译协调的知识。因此，研究对于理解压力如何促进疾病的进展非常重要。代谢和神经退行性疾病，并允许开发新的诊断策略和治疗。