Role of the autophagy-inducing kinases ULK1/2 in ER export and protein trafficking

自噬诱导激酶 ULK1/2 在 ER 输出和蛋白质运输中的作用

• 批准号: 10391339
• 负责人: MONDIRA KUNDU
• 金额: $ 44.88万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391339
• 关键词: Address; Affect; Amino Acid Transporter; Amino Acids; Autophagocytosis; Autophagosome; Biochemical; Bypass; Cell Line; Cell Surface Proteins; Cell membrane; Cells; Communication; Complex; Cues; Data; Disease; Eating Disorders; Endoplasmic Reticulum; Essential Amino Acids; FRAP1 gene; Goals; Golgi Apparatus; Homeostasis; Impairment; Kinetics; Lead; Link; Mediating; Mental Depression; Metabolic; Metabolic stress; Modeling; Molecular; Neurons; Nutrient; Pathway interactions; Pharmacology; Phosphorylation; Phosphotransferases; Post-Translational Protein Processing; Process; Proteins; Risk; Role; Route; Schizophrenia; Series; Serotonin; Serotonin Production; Shapes; Signal Transduction; Starvation; Stress; Structure; Surface; System; Vesicle; antiporter; autism spectrum disorder; cell type; experimental study; genetic approach; inhibitor; insight; isoleucylvaline; mutant; neuronal circuitry; neuropsychiatric disorder; neurotransmission; nutrient deprivation; phenylalanylleucine; protein transport; real time monitoring; response; reuptake; scaffold; serotonin transporter; trafficking; uptake

PROJECT SUMMARY/ABSTRACT Unc51-like kinases 1 and 2 (ULK1/2) are best characterized for their roles in autophagy, an evolutionarily conserved response to starvation that allows cells to recycle cellular components. We recently discovered that, in addition to their well-established roles in autophagy, ULK1/2 regulate endoplasmic reticulum (ER)-to-Golgi trafficking. This molecular connection between autophagy and COPII transport may answer the long-standing question as to what mechanism(s) underlie the differential export of secretory cargoes from the ER in response to metabolic cues. Because ULK1/2 regulates ER-to-Golgi trafficking under basal conditions, initiates autophagosome formation near ERESs in response to metabolic stress, and is a direct target of nutrient- and energy-sensing kinases (i.e., mTOR and AMPK), it is poised to coordinate metabolic cues and protein trafficking from the ER. Our preliminary studies suggest that cargoes destined for the plasma membrane are differentially trafficked in response to metabolic stress, and this switch may depend on ULK1/2 activity. ER export of some cargoes (exemplified by the serotonin transporter SERT) decreases in response to metabolic stress, whereas trafficking of other cargoes (exemplified by the amino acid transporter CD98) increases. Although nutrient-dependent ER export is of importance to a broad range of cell types, the potential implications of ULK1/2's role in regulating this process are immediately relevant in serotonergic neurons, which not only rely on SERT to terminate serotonergic neurotransmission but also rely on the regulated uptake of amino acids by CD98 for serotonin production. Serotonin signaling is linked to nutrient availability, and dysregulation of serotonin signaling leads to perturbations in neuronal circuits that increase the risk of developing neuropsychiatric disorders, including autism, schizophrenia, depression, and eating disorders. This proposal seeks to answer the following questions from the perspective of ULK1/2: How is COPII-dependent ER-to-Golgi trafficking suppressed in response to nutrient deprivation? How does nutrient deprivation stimulate the ER export of certain cargoes? Defining ULK1/2 as a potential mechanistic link between nutrient availability and key aspects of serotonergic neurotransmission – namely, SERT-mediated serotonin reuptake and the production of serotonin via CD98-mediated Trp uptake – may provide a model of how neurons coordinate metabolic signals with neurotransmission to maintain homeostasis.

项目总结/摘要 Unc 51样激酶1和2（ULK 1/2）的最佳特征是它们在自噬中的作用，这是进化上的一个重要特征。 对饥饿的保守反应，允许细胞再循环细胞成分。我们最近发现， 除了它们在自噬中公认作用外，ULK 1/2还调节内质网（ER）至高尔基体 贩卖人口自噬和COPII转运之间的这种分子联系可能回答了长期存在的 问题是什么机制的基础上的差异出口的分泌货物从ER的反应 代谢线索。由于ULK 1/2在基础条件下调节ER向高尔基体的运输， 自噬体在ERES附近响应代谢应激而形成，并且是营养和 能量感应激酶（即，mTOR和AMPK），它准备协调代谢线索和蛋白质 从急诊室走私我们的初步研究表明，运往质膜的货物是 这种转换可能依赖于ULK 1/2活性。儿 一些货物的出口（以5-羟色胺转运蛋白SERT为例）在代谢反应中减少， 应激，而其他货物（以氨基酸转运蛋白CD 98为例）的运输增加。 虽然营养依赖性ER输出对广泛的细胞类型都很重要，但其潜在的 ULK 1/2在调节这一过程中的作用的意义与多巴胺能神经元直接相关， 不仅依赖于SERT来终止多巴胺能神经传递，而且依赖于对 氨基酸通过CD 98用于5-羟色胺的产生。5-羟色胺信号与营养物质的可用性有关， 5-羟色胺信号的失调导致神经元回路的扰动，增加了 发展神经精神障碍，包括自闭症、精神分裂症、抑郁症和饮食失调。这 建议从ULK 1/2的角度回答以下问题：COPII如何依赖 ER到高尔基体的运输在营养剥夺中受到抑制？营养缺乏如何刺激 某些货物的出口？将ULK 1/2定义为营养素可用性之间的潜在机制联系 以及血清素能神经传递的关键方面--即SERT介导的血清素再吸收和 通过CD 98介导的色氨酸摄取产生5-羟色胺-可能提供神经元如何协调的模型 代谢信号与神经传递来维持体内平衡。