Regulation of Axonal Retrograde Signaling by Palmitoylation

棕榈酰化对轴突逆行信号传导的调节

• 批准号: 9147493
• 负责人: Gareth Thomas
• 金额: $ 34.13万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9147493
• 关键词: Acyltransferase; Address; Afferent Neurons; Axon; Axotomy; Binding; Carrier Proteins; Cell Nucleus; Cell membrane; Cells; Complex; Development; Distal; Employee Strikes; Enzymes; Goals; Growth; IL6ST gene; Injury; Janus kinase; Lead; Leucine Zippers; Link; Lipids; Location; Maps; Microfluidics; Modification; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Palmitic Acylation Site; Pathway interactions; Peripheral; Phenocopy; Phosphorylation; Phosphotransferases; Proteins; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Site; Stat3 protein; Stimulus; Surface; Synapses; Testing; Vesicle; Work; axon injury; axon regeneration; base; extracellular; improved; in vivo; insight; knock-down; mutant; nerve injury; neurodevelopment; neuronal cell body; neurotransmission; novel; novel therapeutics; palmitoylation; prevent; programs; protein transport; public health relevance; receptor; regenerative; research study; response; response to injury; small hairpin RNA; trafficking

 DESCRIPTION (provided by applicant): The long-term goal of this project is to define molecular mechanisms by which long-distance signals are conveyed in axons. Retrograde signals from distal axons to neuronal nuclei are critical to activate transcriptional programs both during neurodevelopment and following nerve injury. These retrograde signals involve physical protein transport, but several retrograde signaling proteins are predicted to be soluble and diffusible and it is unclear how they convey long distance directional signals. This project seeks to test the novel hypothesis that the protein-lipid modification palmitoylation allows otherwise soluble signaling proteins to 'hitchhike' on trafficking vesicles and thus convey retrograde signals. Our preliminary studies support this hypothesis and suggest that direct palmitoylation is essential for retrograde signaling by Dual Leucine-zipper Kinase (DLK) in response to injury. Aim 1 of this proposal will define the cellular and molecular basis for this finding, in particularby testing the novel hypothesis that palmitoylation is a unique 'dual control' mechanism that regulates both DLK localization and kinase activity. We will then define the importance of palmitoylation for DLK's 'downstream' functional roles in axonal regeneration post-injury. Aim 2 addresses how palmitoylation regulates signaling by a second pathway involving Janus Kinase (JAK) and JAK's substrate Signal Transducer and Activator of Transcription-3 (STAT3). Importantly, JAK-STAT3 signaling requires dynamic relocalization of these proteins from their steady-state locations in response to extracellular stimuli. This Aim will thus determine whether palmitoylation is broadly required for retrograde signaling and will also define the importance of stimulus-dependent palmitoylation for dynamic retrograde trafficking. Aim 3 seeks to identify the palmitoyl acyltransferases (PATs) that control palmitoylation of retrograde signaling proteins, focusing on whether the axonally-enriched PATs DHHC5 and DHHC8 are key regulators of JAK/STAT3's 'upstream' receptor gp130. The overall impact of this proposal will be to define a novel molecular mechanism that is critical to convey axonal retrograde signals. The focus of this work on responses to axonal injury could lead to new therapies to improve regenerative growth, while the discoveries made should also enhance our broader understanding of axon development and of neuropathological conditions linked to impaired axonal trafficking.

 描述（由申请人提供）：该项目的长期目标是定义在轴突中传递长距离信号的分子机制。从远端轴突到神经元核的逆行信号对于激活转录程序至关重要 在神经发育期间和神经损伤后。这些逆行信号涉及物理蛋白质运输，但预计几种逆行信号蛋白是可溶和可扩散的，并且尚不清楚它们如何传递长距离定向信号。该项目旨在测试新的假设，即蛋白质-脂质修饰棕榈酰化允许其他可溶性信号蛋白“搭便车”在运输囊泡上，从而传递逆行信号。我们的初步研究支持这一假设，并表明直接棕榈酰化对于双亮氨酸拉链激酶 (DLK) 响应损伤的逆行信号传导至关重要。该提案的目标 1 将定义这一发现的细胞和分子基础，特别是通过测试棕榈酰化是调节 DLK 定位和激酶活性的独特“双重控制”机制的新假设。然后我们将定义棕榈酰化对于 DLK 在损伤后轴突再生中的“下游”功能作用的重要性。目标 2 探讨棕榈酰化如何通过涉及 Janus 激酶 (JAK) 和 JAK 底物信号转导器和转录激活剂 3 (STAT3) 的第二条途径调节信号传导。重要的是，JAK-STAT3 信号传导需要这些蛋白质从其稳态位置动态重新定位，以响应细胞外刺激。因此，该目标将确定棕榈酰化是否是逆行信号传导广泛需要的，并且还将确定刺激依赖性棕榈酰化对于动态逆行运输的重要性。目标 3 旨在鉴定控制逆行信号蛋白棕榈酰化的棕榈酰酰基转移酶 (PAT)，重点关注轴突富集的 PAT DHHC5 和 DHHC8 是否是 JAK/STAT3“上游”受体 gp130 的关键调节因子。该提案的总体影响将是定义一种对于传递轴突逆行信号至关重要的新型分子机制。这项工作的重点是对轴突损伤的反应，可能会带来改善再生生长的新疗法，而所取得的发现也应该增强我们对轴突发育和与轴突运输受损相关的神经病理状况的更广泛的理解。