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.

项目摘要/摘要 Unc51-like kinase1和2(ULK1/2)因其在自噬中的作用而被最好地描述，在进化过程中 对饥饿的保守反应，允许细胞循环利用细胞成分。我们最近发现， 除了在自噬中已有的作用外，ULK1/2还调节内质网(ER)到高尔基体 贩卖人口。自噬和COPII运输之间的这种分子联系可能解释了长期存在的 问题：是什么机制(S)作为回应，导致了ER秘密货物的差异出口 对新陈代谢的提示。因为ULK1/2在基本条件下调节ER到高尔基体的交易，所以发起人 自噬小体在ERES附近形成以响应代谢应激，并且是营养和 能量敏感激酶(即mTOR和AMPK)，它可以协调代谢信号和蛋白质 从急诊室贩卖人口。我们的初步研究表明，运往质膜的货物 这种转换可能取决于ULK1/2的活性。呃 一些货物的出口(以5-羟色胺转运体SERT为例)因代谢而减少 压力，而其他货物的贩运(例如氨基酸转运体CD98)增加。 尽管营养依赖的内质网输出对多种细胞类型都很重要，但潜在的 ULK1/2‘S在调节这一过程中的作用与5-羟色胺能神经元直接相关。 不仅依赖SERT终止5-羟色胺能神经传递，还依赖于调节摄取 氨基酸由CD98产生，用于5-羟色胺的产生。5-羟色胺信号与营养供应有关，而且 5-羟色胺信号的失调导致神经元回路的扰动，从而增加了 出现神经精神障碍，包括自闭症、精神分裂症、抑郁症和进食障碍。这 提案试图从ULK1/2的角度回答以下问题：COPII如何依赖 因营养匮乏而抑制从内质网到高尔基体的交易？营养缺乏是如何刺激 某些货物的紧急救援出口？将ULK1/2定义为养分有效性之间的潜在机制联系 和5-羟色胺能神经传递的关键方面--即SERT介导的5-羟色胺再摄取和 通过CD98介导的色氨酸摄取产生5-羟色胺--可能为神经元如何协调提供一个模型 代谢信号与神经传递有关，以维持体内平衡。