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MECHANISMS OF AP-3 FUNCTION IN VESICLE FORMATION AND GOLGI MATURATION

AP-3 在囊泡形成和高尔基体成熟中的功能机制

基本信息

批准号：
10226217
负责人：
Alexey Jarrell Merz
金额：
$ 46.65万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2019-09-12 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226217
关键词：
Animal Model Architecture Binding Biochemical Biochemical Genetics Biochemistry Biological Biological Models Biological Process Bypass Capsid Cell physiology Cells Coated vesicle Communicable Diseases Complex Data Defect Destinations Disease Early Endosome Electron Microscopy Endocytosis Endosomes Epilepsy Eukaryotic Cell Event Fluorescence Microscopy Foundations Functional disorder Genetic Genetic Diseases Goals Golgi Apparatus HIV HIV-1 Hermanski-Pudlak Syndrome Human Impairment Lesion Link Lipids Location Lysosomes Membrane Microscopic Mission Modeling Molecular Morphology Multivesicular Body National Institute of General Medical Sciences Organelles Outcome Pathway interactions Pharmacology Play Prevention Process Proteins Proteomics Public Health Publishing Research Role Saccharomyces cerevisiae Saccharomycetales Site Sorting - Cell Movement Structure Surveys Syndrome System TFAP2A gene Testing Transcription Factor AP-1 Ubiquitination Vacuole Vesicle Viral Virus Assembly Work Yeasts base cofactor disease diagnosis follow-up functional genomics genetic approach imaging approach innovation late endosome novel prevent programs spatiotemporal trafficking trans-Golgi Network ubiquitin ligase ubiquitin-protein ligase vesicle transport yeast genetics

项目摘要

PROJECT SUMMARY The secretory pathway folds, assembles, and sorts membrane and secreted proteins and targets them to a variety of locations inside and outside the cell. The `Grand Central Station' of the cell is the trans Golgi network (TGN), an incredibly dynamic and complex structure that packages cargo into separate containers and dispatches them to their terminal destinations. The AP-3 trafficking complex sorts cargo from endosomes or the Golgi into containers bound for endolysosomal compartments, bypassing the endosomal multivesicular body and ESCRT pathway. AP-3 is needed for productive assembly of HIV and other viral capsids. Genetic lesions impairing AP-3 function cause multiple diseases, including Hermansky-Pudlak Syndrome type 2 and an epilepsy-like syndrome. Despite its importance, remarkably little is known about the mechanisms of AP-3 function. In this collaborative Project, we exploit published and unpublished genetic, cell biological, and biochemical advances, and employ state of the art imaging approaches, to dissect the mechanisms of AP-3 budding and the consequences of AP-3 function for the overall dynamics of the TGN, in the model organism Saccharomyces cerevisiae. In Aim 1, we build on proteomic surveys, functional genomic surveys, and follow-up analyses, wich identify new candidate AP-3 cofactors including a ubiquitin ligase. We will use these advances to test hypotheses about the assembly, maturation, and dispatch of AP-3 vesicles from the TGN. In Aim 2, we build on preliminary findings showing that disruption of AP-3 activity causes striking and unexpected global perturbations of Golgi architecture. We hypothesize, based on published and unpublished data, that distinct carriers exit the TGN in a programmed, sequential manner, with AP-3 carriers departing early. We will further test this model and dissect the molecular mechanisms though which the sequence of events is programmed. Together, these studies should establish new paradigms for AP-3 vesicle formation and for organelle maturation dynamics in the Golgi-endolysosomal system.

项目总结