The ubiquitin proteasome system in ER quality control

项目总结/摘要 在内质网中合成的蛋白质的折叠和组装是 由质量控制设备密切监控， 产物被泛素-蛋白酶体系统降解， 这一过程称为内质网相关降解（ERAD）。的 本项目的长期目标是阐明ERAD 识别并摧毁目标在上一个融资周期，我们 成功地实施了大规模的功能基因组分析， 哺乳动物ERAD系统，使我们能够进行无偏分析， 哺乳动物中的底物选择性ERAD。这些数据导致了重要的发现 关于底物分类和输送到HRD的机制1 错位/连接酶和非常规泛素缀合在偶联中的作用 从错位到退化本申请中提出的研究 利用最先进的技术来扩展这些发现， 成功将带来一个详细的分子水平的理解分诊， 早期分泌途径的质量控制。

Project Summary/Abstract Folding and assembly of proteins synthesized in the endoplasmic reticulum is closely monitored by a quality control apparatus that diverts folding-defective products to the cytosol to be degraded by the ubiquitin-proteasome system by a process known as endoplasmic reticulum-associated degradation (ERAD). The long-term goal of this project is to elucidate the mechanisms by which ERAD recognizes and destroys its targets. In the previous funding period we successfully implemented a large scale functional genomic analysis of the mammalian ERAD system that allowed us to perform unbiased analysis of substrate-selective ERAD in mammals. These data led to critical discoveries about the mechanisms of substrate triage and delivery to the HRD1 dislocon/ligase and the role of unconventional ubiquitin conjugation in coupling dislocation to degradation. The studies proposed in the present application harness state-of-the-art technologies that extend these discoveries and if successful will bring about a detailed molecular-level understanding of triage and quality control in the early secretory pathway.