Vps4 and the MVB sorting pathway.

Vps4 和 MVB 排序路径。

• 批准号: 8228067
• 负责人: MARKUS BABST
• 金额: $ 33.64万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-05 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228067
• 关键词: ATP phosphohydrolase; Affect; Amino Acids; Carrier Proteins; Cell Communication; Cell Proliferation; Cell Surface Proteins; Cell division; Cell membrane; Cell physiology; Cells; Cellular Membrane; Complex; Cytokinesis; Cytoplasmic Structures; Data; Disease; Down-Regulation; Electron Transport Complex III; Endocytosis; Ensure; Event; Filament; Goals; Growth; HIV; HIV-1; Human Cell Line; Immune response; Knowledge; Link; Malignant Neoplasms; Mediating; Membrane; Membrane Proteins; Metabolic; Metabolism; Multivesicular Body; Nutrient; Pathology; Pathway interactions; Peptide Initiation Factors; Phosphotransferases; Play; Principal Investigator; Process; Protein Biosynthesis; Proteins; Reaction; Recycling; Regulation; Research; Retroviridae; Role; Set protein; Site; Sorting - Cell Movement; Starvation; Structure; System; Translation Initiation; Translations; Up-Regulation; Vesicle; Viral; Virus Diseases; base; cell growth; genetic regulatory protein; human disease; insight; novel; particle; protein complex; protein degradation; protein function; public health relevance; research study; response; uptake

DESCRIPTION (provided by applicant): The degradation of membrane proteins via the multivesicular body (MVB) pathway plays an essential role in regulating cell-surface proteins. As a consequence, numerous cellular functions, such as nutrient uptake, cell- cell communication and immune response are dependent on MVBs. The formation of MVBs is executed by a group of highly conserved protein complexes called ESCRTs (Endosomal Sorting Complex Required for Transport). ESCRTs perform a unique membrane budding event, which results in vesicle formation in the lumen of the MVB. Retroviruses, such as HIV, co-opt the ESCRT machinery during viral infection to complete formation of viral particles via a similar membrane budding event at the plasma membrane. Furthermore, cytokinesis requires the ESCRT-dependent fusion of the plasma membrane in order to form two separate cells. Our recent studies indicate that ESCRT function and protein translation are tightly connected. On one hand, the MVB pathway degrades proteins and recycles amino acids for further use in protein translation. On the other hand, we observed that translation efficiency regulates ESCRT function by increasing or decreasing the cellular levels of the ESCRT regulatory protein Ist1. High amino acid levels in the cell increase translation and thus the cellular concentration of Ist1, which in turn decreases ESCRT activity and protein degradation via the MVB pathway. In contrast, starvation induces protein degradation via the MVB pathway by lowering Ist1 levels and by increasing endocytosis of numerous plasma membrane proteins. In addition, we observed that amino acid starvation resulted in the relocalization of some ESCRT components and translation-initiation factors to a filamentous structure, which we termed STICS (STarvation Induced Cytoplasmic Structure). We propose that STICS formation might facilitate the switch from general translation to the specialized protein translation occurring during starvation. Together, our preliminary experiments uncovered a complex regulatory system that coordinates the necessary changes in the activity of translation, endocytosis and protein turnover in the MVB pathway to ensure survival under starvation conditions. The goal of the proposed research is to characterize this regulatory system and to determine how malfunction of this system affects cellular growth and adaptation. PUBLIC HEALTH RELEVANCE: The proposed project studies how cellular metabolism regulates the function of a set of proteins, called ESCRTs, that are involved in protein turnover, cell division and formation of retroviruses. This knowledge has the potential to help us understand on a cellular level how nutrients might affect the pathology of human diseases such as HIV and cancer.

描述（由申请人提供）：通过多个体体（MVB）途径降解膜蛋白在调节细胞表面蛋白中起着至关重要的作用。结果，许多细胞功能，例如营养摄取，细胞通信和免疫反应取决于M​​VB。 MVB的形成是由一组称为ESCRT的高度保守的蛋白质复合物（运输所需的内体分类复合物）执行的。 ESCRT执行独特的膜出现事件，从而导致MVB管腔中的囊泡形成。逆转录病毒，例如HIV，在病毒感染过程中选择ESCRT机械，以通过质膜上的类似膜出芽事件完成病毒颗粒的形成。此外，细胞因子需要质膜的依赖性融合，以形成两个单独的细胞。我们最近的研究表明，ESCRT功能和蛋白质翻译密切相关。一方面，MVB途径降解蛋白质和回收氨基酸，以在蛋白质翻译中进一步使用。另一方面，我们观察到翻译效率通过增加或降低ESCRT调节蛋白IST1的细胞水平来调节ESCRT功能。细胞中的高氨基酸水平增加了翻译，因此IST1的细胞浓度又会通过MVB途径降低ESCRT活性和蛋白质降解。相反，饥饿通过降低IST1水平和增加众多质膜蛋白的内吞作用，通过MVB途径诱导蛋白质降解。此外，我们观察到氨基酸饥饿导致某些ESCRT成分和翻译引入因子的重新定位为丝状结构，我们称之为Stics（饥饿诱导的细胞质结构）。我们建议Stics的形成可能有助于从一般翻译转变为饥饿期间发生的专用蛋白质翻译。我们的初步实验共同发现了一个复杂的调节系统，该系统协调了MVB途径中翻译，内吞作用和蛋白质更新的必要变化，以确保在饥饿条件下存活。拟议研究的目的是表征该调节系统，并确定该系统的故障如何影响细胞的生长和适应。 公共卫生相关性：拟议的项目研究细胞代谢如何调节一组称为ESCRT的蛋白质的功能，这些蛋白质与蛋白质更新，细胞分裂和逆转录病毒的形成有关。这些知识有可能帮助我们在细胞水平上了解营养如何影响艾滋病毒和癌症等人类疾病的病理。