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: 9974591
• 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/9974591
• 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.

项目总结/文摘