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Cytosolic-Vesicle-Vacuolar Protein Degradation Pathway

胞浆-囊泡-液泡蛋白降解途径

基本信息

批准号：
7904166
负责人：
HUI-LING CHIANG
金额：
$ 30.34万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7904166
关键词：
Address Aging Alzheimer&apos s Disease Autophagocytosis Binding Carbon Cell Cycle Cells Cessation of life Complex Cyclic AMP Defect Degradation Pathway Development Disease Enzymes Epilepsy Excision Fructose Fructose-1,6-Bisphosphatase Futile Cycling Genes Glucose Goals Homologous Gene Human Huntington Disease Isocitrate Lyase Isocitrates Lead Link Lysosomes Malate Dehydrogenase Malignant Neoplasms Mediating Metabolic Control Microtubules Molecular Mus Mutation Neuromuscular Diseases Nutrient Organelles Parkinson Disease Pathway interactions Play Process Proteins Research Personnel Role Signal Pathway Signaling Molecule Site Source Starvation System Testing Therapeutic Transcriptional Regulation Vacuole Vesicle Work Yeasts brain malformation cell growth gene function isocitrate lissencephaly multicatalytic endopeptidase complex neuromuscular overexpression prevent programs protein complex protein degradation protein protein interaction research study therapeutic development trafficking

项目摘要

DESCRIPTION (provided by applicant): Protein degradation is critical for cell cycle division, cell growth control, transcriptional regulation and metabolic control. Autophagy is a process whereby lysosomes degrade cytosolic proteins and organelles when cells are starved of nutrients. Defects or changes in autophagy have been linked to cancer development, neuromuscular dystrophies and aging. Multiple forms of autophagy exist, and a unique autophagy pathway has been identified in our lab. The gluconeogenic enzyme fructose-1,6-bisphosphatase (FBPase) is degraded when yeast cells are shifted from poor carbon sources to fresh glucose, and this degradation prevents energy futile cycles that are harmful to cells. FBPase can be degraded either in the proteasome or in the vacuole depending on the duration of starvation. For the vacuolar pathway, FBPase is first targeted to Vid vesicles and then to the vacuole. A number of VID genes function in both degradation pathways and they are evolutionary conserved. The Vid pathway is utilized for multiple cargo proteins including isocitrate lysase, phosphoenopyruvate carboxykinase and malate dehydrogenase. Our long-term goal is to understand the mechanisms underlying the vacuolar dependent pathway of FBPase degradation. The objective of this application is to understand why FBPase switches degradation from the proteasome to the vacuole. Our central hypothesis is that the switch is controlled by multiple protein complexes that can be activated or inactivated depending upon the duration of starvation. We plan to test this hypothesis by pursuing the following aims. 1. We will study why the Vid vesicle trafficking pathway is inactive in short termed starved cells. Is this because of an inactive cAMP signaling pathway, the absence of Vid vesicles, or incompetent Vid vesicles? 2. FBPase physically interacts with components of the Tori complex (TORC1). We will study how Tori regulates the vacuolar pathway. 3. Vid28p and VidSOp form a stable complex. We will study how this complex regulates both degradation pathways. The completion of the proposed experiments will enhance our understanding regarding how these two major proteolytic pathways are regulated. This may provide therapeutic advantages to eliminate abnormal proteins that accumulate in Parkinson's disease, Huntington's disease or other pathological conditions.

描述（由申请人提供）：蛋白质降解对于细胞周期分裂、细胞生长控制、转录调节和代谢控制至关重要。自噬是当细胞缺乏营养时溶酶体降解胞浆蛋白和细胞器的过程。自噬的缺陷或变化与癌症发展、神经肌肉营养不良和衰老有关。存在多种形式的自噬，并且我们的实验室已经确定了一种独特的自噬途径。当酵母细胞从贫乏碳源转移到新鲜葡萄糖时，糖异生酶果糖-1,6-双磷酸酶 (FBPase) 会被降解，这种降解可以防止对细胞有害的能量无用循环。 FBPase 可以在蛋白酶体或液泡中降解，具体取决于饥饿的持续时间。对于液泡途径，FBPase 首先靶向 Vid 囊泡，然后靶向液泡。许多 VID 基因在两种降解途径中都发挥作用，并且它们在进化上是保守的。 Vid 途径用于多种货物蛋白，包括异柠檬酸裂解酶、磷酸烯丙酮酸羧激酶和苹果酸脱氢酶。我们的长期目标是了解 FBPase 降解的液泡依赖性途径的潜在机制。此应用的目的是了解为什么 FBPase 将降解从蛋白酶体切换到液泡。我们的中心假设是，这种开关是由多种蛋白质复合物控制的，这些蛋白质复合物可以根据饥饿的持续时间被激活或失活。我们计划通过追求以下目标来检验这一假设。 1. 我们将研究为什么 Vid 囊泡运输途径在短期饥饿细胞中不活跃。这是因为 cAMP 信号通路不活跃、缺乏 Vid 囊泡或 Vid 囊泡功能不全吗？ 2. FBPase 与 Tori 复合体 (TORC1) 的成分发生物理相互作用。我们将研究 Tori 如何调节液泡通路。 3. Vid28p和VidSOp形成稳定的复合物。我们将研究这种复合物如何调节这两种降解途径。所提出的实验的完成将增强我们对这两种主要蛋白水解途径如何调节的理解。这可能提供治疗优势，以消除帕金森病、亨廷顿病或其他病理状况中积累的异常蛋白质。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The heat shock protein Ssa2p is required for import of fructose-1, 6-bisphosphatase into Vid vesicles.

将果糖-1, 6-双磷酸酶导入 Vid 囊泡需要热休克蛋白 Ssa2p。

DOI：
10.1083/jcb.150.1.65
发表时间：
2000-07-10
期刊：
The Journal of cell biology
影响因子：
0
作者：
Brown CR;McCann JA;Chiang HL
通讯作者：
Chiang HL

Vacuole import and degradation pathway: Insights into a specialized autophagy pathway.

DOI：
10.4331/wjbc.v2.i11.239
发表时间：
2011-11-26
期刊：
World journal of biological chemistry
影响因子：
0
作者：
Alibhoy, Abbas A;Chiang, Hui-Ling
通讯作者：
Chiang, Hui-Ling

Biochemical analysis of fructose-1,6-bisphosphatase import into vacuole import and degradation vesicles reveals a role for UBC1 in vesicle biogenesis.

对果糖-1,6-双磷酸酶输入液泡输入和降解囊泡的生化分析揭示了 UBC1 在囊泡生物发生中的作用。

DOI：
10.1074/jbc.m001767200
发表时间：
2001
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Shieh,HL;Chen,Y;Brown,CR;Chiang,HL
通讯作者：
Chiang,HL

The TOR complex 1 is required for the interaction of multiple cargo proteins selected for the vacuole import and degradation pathway.

DOI：
10.4161/cib.3.6.13241
发表时间：
2010-11-01
期刊：
Communicative & integrative biology
影响因子：
0
作者：
Alibhoy, Abbas A;Chiang, Hui-Ling
通讯作者：
Chiang, Hui-Ling

Vid22p, a novel plasma membrane protein, is required for the fructose-1,6-bisphosphatase degradation pathway.

Vid22p 是一种新型质膜蛋白，是果糖 1,6-二磷酸酶降解途径所必需的。

DOI：
10.1242/jcs.115.3.655
发表时间：
2002
期刊：
Journal of cell science
影响因子：
4
作者：
Brown,CRandell;McCann,JamesonA;Hung,GrahamGuo-Chiuan;Elco,ChristopherP;Chiang,Hui-Ling
通讯作者：
Chiang,Hui-Ling