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Ubiquitin-Dependent Protein Regulation and Quality Control of the Lysosomal Membrane

溶酶体膜的泛素依赖性蛋白质调节和质量控制

基本信息

批准号：
10018043
负责人：
Ming Li
金额：
$ 32.76万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018043
关键词：
Affect Aging Alzheimer&apos s Disease Autophagocytosis Binding Binding Proteins Binding Sites Biological Assay Biological Models Birth Cell Death Cells Clustered Regularly Interspaced Short Palindromic Repeats Complement Complex Cues Cycloheximide Defect Degradation Pathway Development Digestion Down-Regulation Endocytosis Functional disorder Goals Homeostasis Human Huntington Disease Inflammation Investigation Knock-out Laboratories Light Link Lysosomal Storage Diseases Lysosomes Mammalian Cell Maps Measures Membrane Membrane Proteins Methods Mitochondria Molecular Mutation Nerve Degeneration Neuraxis Neurodegenerative Disorders Organelles Paper Parkinson Disease Pathogenicity Pathway interactions Patients Physiological Play Proteins Proteome Proteomics Publications Quality Control Recycling Regulation Research Role Signal Transduction Sirolimus Small Interfering RNA Sorting - Cell Movement Stress Structure Symptoms Techniques Ubiquitin Ubiquitination Vacuole Yeasts age related neurodegeneration base cell growth detection of nutrient exhaustion follow-up infancy loss of function lysosome membrane novel protein aggregation protein degradation recruit response screening treatment strategy ubiquitin-protein ligase yeast protein yeast two hybrid system

项目摘要

Project Summary The lysosome is an essential organelle responsible for the digestion and recycling of materials delivered by endocytosis and autophagy. It also plays important roles in nutrient sensing and control of cell growth by regulating the localization and activity of mTORC1 signaling complex. Because of its importance, lysosome dysfunction leads to ~ 50 types of lysosomal storage diseases (LSDs) and contributes to many aging-related neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases. Despite exhaustive research on how proteins are delivered to lysosomes, how lysosomes regulate their own membrane proteins remains poorly understood. However, studying this question will reveal how cells maintain a healthy lysosome during stresses and aging. Our long-term goal is to understand these fundamental questions using both yeast and mammalian cells as model systems. Recently, we discovered a ubiquitin- and ESCRT- dependent down-regulation pathway for lysosome (vacuole) membrane proteins in yeast. Follow-up investigations in our laboratory led us to hypothesize that the ubiquitin- and ESCRT- dependent degradation pathway is a general conserved mechanism to regulate the lysosome membrane composition from yeast to human. Consistently, recent proteomic studies identified multiple E3 ubiquitin ligases on the human lysosome membrane. Furthermore, the ESCRT machinery was shown to be recruited to the human lysosome membrane. In this proposed research, we plan to expand our initial findings by pursuing three specific aims. Our Aim 1 will investigate how TORC1 regulates the vacuole membrane proteome via the ubiquitin- and ESCRT-dependent pathway in yeast. Our Aim 2 will study how yeast vacuole membrane E3 ligases recognize their membrane substrates at both structure and function level. Our Aim 3 will study how human lysosomes turnover their membrane proteins. Our research will shed light on the development of new treatment strategies for LSDs and lysosome-related neurodegenerative diseases.

项目总结