The ubiquitin proteasome system in ER quality control

项目摘要/摘要 内质网合成的蛋白质的折叠和组装 由质量控制装置严密监控，将有折叠缺陷的 被泛素-蛋白酶体系统降解的产物进入胞浆 这一过程称为内质网相关降解(ERAD)。这个 该项目的长期目标是阐明ERAD 识别并摧毁它的目标。在上一个资助期，我们 成功地实施了大规模的功能基因组分析 哺乳动物的ERAD系统，使我们能够对 哺乳动物中的底物选择性ERAD。这些数据导致了关键的发现 关于底物分流和递送到Hrd1的机制 错位/连接酶与非常规泛素偶联的作用 从错位到退化。本申请中提议的研究 利用最先进的技术来扩展这些发现，如果 成功将带来对分诊和分流的详细的分子水平的理解 早期分泌途径的质量控制。 好了！

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. !