Cytosolic-Vesicle-Vacuolar Protein Degradation Pathway

胞浆-囊泡-液泡蛋白降解途径

• 批准号: 7259781
• 负责人: HUI-LING CHIANG
• 金额: $ 30.64万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7259781
• 关键词: Cytosolic; Vesicle; Vacuolar; Protein; Degradation

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(申请人提供)：蛋白质降解对细胞周期分裂、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物质时，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的发展、神经肌肉营养不良和衰老有关。自噬存在多种形式，在我们的实验室中已经发现了一种独特的自噬途径。当酵母细胞从贫乏的碳源转移到新鲜的葡萄糖时，葡萄糖异生酶果糖-1，6-二磷酸酶(FBPase)被降解，这种降解防止了对细胞有害的能量无用循环。FBPase可以在蛋白酶体或液泡中被降解，这取决于饥饿的持续时间。对于液泡途径，FBPase首先定位于VID小泡，然后定位于液泡。许多VID基因在这两条退化途径中发挥作用，并且它们在进化上是保守的。VID途径被用于多种货物蛋白，包括异柠檬酸裂解酶、磷酸烯丙酮酸羧酸激酶和苹果酸脱氢酶。我们的长期目标是了解FBPase降解的液泡依赖途径的潜在机制。这项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，开关是由多个蛋白质复合体控制的，根据饥饿的持续时间，这些复合体可以被激活或失活。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是不活跃的。这是因为不活跃的cAMP信号通路，没有VD小泡，还是没有功能的VID小泡？2.FBPase与环状复合体的成分(TORC1)物理上相互作用。我们将研究Tori如何调节液泡途径。3.Vid28p与VidSOp形成稳定的复合体。我们将研究这种复合体如何调节这两条降解途径。拟议中的实验的完成将加深我们对这两个主要蛋白分解途径如何调控的理解。这可能会为消除帕金森氏症、亨廷顿病或其他病理状态中积聚的异常蛋白质提供治疗优势。