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Death and Destruction: How the Ubiquitin Proteasome System Executes Linker Cell-type Death

死亡与破坏：泛素蛋白酶体系统如何执行连接细胞型死亡

基本信息

批准号：
10678636
负责人：
Lauren Bayer Horowitz
金额：
$ 7.43万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-28 至 2024-09-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10678636
关键词：
Animals Antibodies Apoptosis Apoptotic Binding Biological Caenorhabditis elegans Caspase Cell Death Cell Death Process Cell Survival Cells Cessation of life Characteristics Chromatin Chromatin Structure Cullin Proteins Data Defect Development Disease Electron Microscopy Embryo Enzymes Epithelial Cells Etiology Exhibits Female Genes Genetic Genetic Epistasis Genetic Screening Genetic Transcription Genetic study Goals Heat shock factor Heterochromatin Histones Homeostasis Homologous Gene Huntington Disease Hybrids Ligase Link Maintenance Malignant Neoplasms Methods Minor Molecular Morphology Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Nuclear Pathway interactions Patients Process Production Proteins RNA interference screen Research Role S-Adenosylhomocysteine S-Adenosylmethionine Site Spinal Spinal Cord Stains Structure Structure of paramesonephric duct System Testing Time Tissues Transferase UBE2D2 gene Ubiquitin Ubiquitin-Conjugating Enzymes Vertebral column Vertebrates Yeasts cell killing cell type chromatin remodeling histone methylation human disease innovation insight live cell imaging male methionine adenosyltransferase multicatalytic endopeptidase complex mutant new therapeutic target novel polyglutamine programs protein degradation reproductive tool tumorigenesis ubiquitin-protein ligase yeast two hybrid system

项目摘要

Project Summary The long-term goal of the proposed research is to understand the cell biological mechanisms that execute non-apoptotic cell death. Programmed cell death is essential for organismal development and homeostasis, and its disruption is associated with many human diseases including cancer and neurodegeneration. Apoptosis is a prominent cell death form, however mutations in key apoptotic regulators only cause minor developmental defects. Non-apoptotic programs, therefore, also exist, but their molecular basis is poorly understood. Linker Cell-type Death (LCD) is a non-apoptotic and caspase-independent cell death process operating in C. elegans development, and its morphological hallmarks have also been observed in vertebrate development and disease. The Ubiquitin Proteasome System (UPS) is a key effector of LCD in C. elegans, but how it executes cell death is unknown. Here I will use powerful genetic and molecular tools in C. elegans to identify and characterize the proteolytic targets of the UPS during LCD and determine how their degradation trigger cell demise. In contrast to apoptosis, which uses caspases that transiently bind their substrates and, remarkably, remain poorly understood, the UPS stably interacts with its substrates. Therefore, the proteins I discover that precipitate cell death may unearth general mechanisms of cellular destruction that also function during apoptosis and disease. Indeed, our preliminary data suggest that one candidate substrate degraded by the UPS is an enzyme required for the maintenance of heterochromatin, which is in line with our previous observations that dying linker cells exhibit an open chromatin state. Therefore, this proposal will investigate the exciting hypothesis that chromatin remodeling, precipitated by the UPS, triggers cellular destruction. I will also discover additional proteolytic targets and mechanisms that execute non-apoptotic cell death with yeast 2-hybrid and RNAi screens. Because dysregulation of the UPS and chromatin state are also linked to tumorigenesis and neurodegenerative diseases, my studies can provide greater understanding of cell death programs disrupted in disease that can point towards new therapeutic targets.

项目总结