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（由适用提供）：该项目的长期目标是定义分子机制，通过这些机制，轴突以轴突传达长距离信号。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之后。这些逆行信号涉及物理蛋白的转运，但是预计几种逆行信号蛋白是固体和扩散的，尚不清楚它们如何传达长距离定向信号。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固体信号蛋白在运输蔬菜上“搭便车”，从而传达逆行信号。我们的初步研究支持这一假设，并表明直接棕榈酰化对于响应损伤的双亮氨酸Zipper激酶（DLK）对逆行信号至关重要。该提案的目标1将定义该发现的细胞和分子基础，特别是测试了新的假设，即棕榈酰化是一种独特的“双重控制”机制，可以调节DLK定位和激酶活性。然后，我们将定义棕榈酰化对DLK在伤害后轴突再生中的“下游”功能的重要性。 AIM 2解决了棕榈酰化如何通过涉及Janus激酶（JAK）和JAK的底物信号换能器和转录3的激活剂的第二个途径调节信号传导（STAT3）。重要的是，JAK-STAT3信号需要从其稳态位置将这些蛋白质的动态重新定位，以响应细胞外刺激。因此，此目标将确定是否要大致需要棕榈酰化才能逆行信号传导，还将确定依赖刺激依赖性棕榈酰化对动态逆行运输的重要性。 AIM 3旨在识别控制逆行信号蛋白的棕榈酰酰基转移酶（PATS），重点是辅助辅助的PATS DHHC5和DHHC8是JAK/STAT3的“ Upstream'受体GP130）的关键调节剂。该提案的总体影响是定义一种新型的分子机制，该机制对于传达轴突逆行信号至关重要。这项工作的重点是对轴突损伤的反应，可能会导致新的疗法改善再生生长，而这些发现还应增强我们对轴突发育和对轴突运输受损的神经病理条件的广泛理解。