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: 9752665
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752665
• 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/antagonist; 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样激酶1和2（ULK1/2）最适合其在自噬中的作用，一种进化。 对饥饿的保守反应，该反应使细胞可以回收细胞成分。我们最近发现， 除了它们在自噬中良好的作用外，ULK1/2还调节内质网（ER） - 到高尔基 贩运。自噬和COPII传输之间的这种分子连接可能会回答长期存在的 关于哪种机制的问题是从急诊室销售秘书货物的差异出口 要代谢提示。由于ULK1/2在基本条件下调节ER到高尔基的贩运，因此 响应代谢应激的ERESS附近的自噬体形成，是营养素和的直接靶标 能量感应激酶（即MTOR和AMPK），它是毒性的，以协调代谢线索和蛋白质 从急诊室贩运。我们的初步研究表明，注定要质膜的货物是 响应代谢应激的差异运输，此切换可能取决于ULK1/2活性。嗯 某些货物的出口（用5-羟色胺转运蛋白Sert示例）响应代谢而减少 压力，而其他货物的运输（以氨基酸转运蛋白CD98为例）则增加。 尽管营养依赖性ER导出对广泛的细胞类型至关重要，但潜力 ULK1/2在确定这一过程中的作用的含义与血清素能神经元有关 不仅依靠Sert终止血清素能神经传递，而且还依靠受监管的吸收 CD98的氨基酸产生5-羟色胺。 5-羟色胺信号传导与养分可用性有关，并且 5-羟色胺信号传导失调会导致神经元电路的扰动，从而增加 发展神经精神疾病，包括自闭症，精神分裂症，抑郁症和饮食失调。这 提案试图从ULK1/2的角度回答以下问题：COPII依赖性如何 ER到高尔基人贩运因养分剥夺而受到抑制？营养剥夺如何刺激 某些货物的ER出口？将ULK1/2定义为营养可用性之间的潜在机械联系 以及血清素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TRP摄取来产生5-羟色胺 - 可以提供神经元如何坐标的模型 具有神经传递的代谢信号维持稳态。