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

• 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
• 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

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。 应激条件激活应激应答激酶，其通过磷酸化 真核起始因子2（eIF 2 α）的α亚基，导致多核糖体解体， 随后的平移衰减。除了削弱翻译，紧张的环境也 激活保护性分子伴侣或热休克蛋白（HSP）的转录。之一 最近在理解压力反应方面的一个主要进展是发现， 应激过程中伴侣蛋白的转录表达不是由细胞经历 大分子损伤，而是由神经系统非自主编排的细胞。 然而，目前还不知道在后生动物的不同细胞之间的平移衰减是否 也通过调节转录的类似细胞-细胞信号通路来协调。在 正在进行的研究，我们发现，虽然转录的伴侣和翻译衰减， 在热休克时，它们相互独立地发生，如伴侣蛋白的转录上调 基因表达、eIF 2 α在热胁迫下的磷酸化。elegans依赖于 电子能系统。这些数据表明，对eIF 2 α磷酸化的β-肾上腺素能控制可能起作用， 以整合生物体细胞对应激的转录和翻译反应。这是 假设我们旨在测试这个建议。具体来说，我们将测试（1）平移衰减是如何 与神经元5-羟色胺释放偶联，以及（2）翻译衰减是否与HSP协调 通过神经元5-HT释放上调。我们预计，这些研究将填补一个关键的空白， 关于后生动物的组织之间在应力下的平移协调的知识。这些 因此，研究对于了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。