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
基本信息
- 批准号:10391339
- 负责人:
- 金额:$ 44.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAmino Acid TransporterAmino AcidsAutophagocytosisAutophagosomeBiochemicalBypassCell LineCell Surface ProteinsCell membraneCellsCommunicationComplexCuesDataDiseaseEating DisordersEndoplasmic ReticulumEssential Amino AcidsFRAP1 geneGoalsGolgi ApparatusHomeostasisImpairmentKineticsLeadLinkMediatingMental DepressionMetabolicMetabolic stressModelingMolecularNeuronsNutrientPathway interactionsPharmacologyPhosphorylationPhosphotransferasesPost-Translational Protein ProcessingProcessProteinsRiskRoleRouteSchizophreniaSeriesSerotoninSerotonin ProductionShapesSignal TransductionStarvationStressStructureSurfaceSystemVesicleantiporterautism spectrum disordercell typeexperimental studygenetic approachinhibitorinsightisoleucylvalinemutantneuronal circuitryneuropsychiatric disorderneurotransmissionnutrient deprivationphenylalanylleucineprotein transportreal time monitoringresponsereuptakescaffoldserotonin transportertraffickinguptake
项目摘要
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.
项目概要/摘要
Unc51 样激酶 1 和 2 (ULK1/2) 最能表征其在自噬中的作用,自噬是一种进化过程
对饥饿的保守反应使细胞能够回收细胞成分。我们最近发现,
除了在自噬中明确的作用外,ULK1/2 还调节内质网 (ER) 至高尔基体
贩运。自噬和 COPII 转运之间的这种分子联系可能会回答长期存在的问题
问题是,作为回应,ER 的分泌货物差异化出口背后的机制是什么?
代谢线索。由于 ULK1/2 在基础条件下调节 ER 至高尔基体的运输,因此启动
ERES 附近自噬体的形成是对代谢应激的反应,是营养物质和营养物质的直接目标。
能量感应激酶(即 mTOR 和 AMPK),它准备协调代谢线索和蛋白质
从急诊室贩运。我们的初步研究表明,运往质膜的货物是
响应代谢应激而进行差异运输,这种转换可能取决于 ULK1/2 活性。急诊室
一些货物的输出(例如血清素转运蛋白 SERT)因代谢而减少
压力,而其他货物(以氨基酸转运蛋白 CD98 为例)的贩运则增加。
尽管营养依赖性内质网输出对于多种细胞类型都很重要,但其潜力
ULK1/2 在调节这一过程中的作用与血清素能神经元直接相关,
不仅依赖 SERT 来终止血清素能神经传递,还依赖于对
CD98 产生氨基酸以产生血清素。血清素信号传导与营养可用性有关,并且
血清素信号传导失调会导致神经元回路扰动,从而增加以下风险:
出现神经精神疾病,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 是如何依赖的
内质网到高尔基体的运输因营养缺乏而受到抑制?营养缺乏如何刺激
某些货物的 ER 出口?将 ULK1/2 定义为养分有效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 介导的血清素再摄取和
通过 CD98 介导的色氨酸吸收产生血清素——可能提供神经元如何协调的模型
代谢信号与神经传递以维持体内平衡。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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MONDIRA KUNDU其他文献
MONDIRA KUNDU的其他文献
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{{ truncateString('MONDIRA KUNDU', 18)}}的其他基金
Mechanisms of Mitochondrial Degradation in Unstressed Mammalian Cells
无应激哺乳动物细胞线粒体降解机制
- 批准号:
9887587 - 财政年份:2020
- 资助金额:
$ 44.88万 - 项目类别:
Mechanisms of Mitochondrial Degradation in Unstressed Mammalian Cells
无应激哺乳动物细胞线粒体降解机制
- 批准号:
10401249 - 财政年份:2020
- 资助金额:
$ 44.88万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 44.88万 - 项目类别:
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 - 财政年份:2018
- 资助金额:
$ 44.88万 - 项目类别:
Regulation of autophagy by AMPK, Hsp90-Cdc37 and Ulk1 in erythroid cells
AMPK、Hsp90-Cdc37 和 Ulk1 在红系细胞中对自噬的调节
- 批准号:
8894563 - 财政年份:2012
- 资助金额:
$ 44.88万 - 项目类别:
Regulation of autophagy by AMPK, Hsp90-Cdc37 and Ulk1 in erythroid cells
AMPK、Hsp90-Cdc37 和 Ulk1 在红系细胞中对自噬的调节
- 批准号:
8689154 - 财政年份:2012
- 资助金额:
$ 44.88万 - 项目类别:
Regulation of autophagy by AMPK, Hsp90-Cdc37 and Ulk1 in erythroid cells
AMPK、Hsp90-Cdc37 和 Ulk1 在红系细胞中对自噬的调节
- 批准号:
8345199 - 财政年份:2012
- 资助金额:
$ 44.88万 - 项目类别:
Regulation of autophagy by AMPK, Hsp90-Cdc37 and Ulk1 in erythroid cells
AMPK、Hsp90-Cdc37 和 Ulk1 在红系细胞中对自噬的调节
- 批准号:
8511812 - 财政年份:2012
- 资助金额:
$ 44.88万 - 项目类别:
Atg1 homologues in autophagy, mitochondrial degradation and erythroid maturation
Atg1 同源物在自噬、线粒体降解和红细胞成熟中的作用
- 批准号:
7294912 - 财政年份:2006
- 资助金额:
$ 44.88万 - 项目类别:
Atg1 homologues in autophagy, mitochondrial degradation and erythroid maturation
Atg1 同源物在自噬、线粒体降解和红细胞成熟中的作用
- 批准号:
7476332 - 财政年份:2006
- 资助金额:
$ 44.88万 - 项目类别:
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