Protein Degradation and Cholesterol Regulation

HMG-CoA还原酶(HMGR)是胆固醇生物合成所必需的内质网驻留蛋白，它的选择性降解在哺乳动物细胞和酵母中都以一种受调控的方式发生。HMGR的调节降解允许控制这种酶的水平，以响应细胞对胆固醇途径产物不断变化的需求。尽管未被开发为临床调节轴，但HMGR的调节降解绝对是HMGR所特有的，因此为设计新的调节策略提供了希望。此外，HMGR被一种鲜为人知的降解途径降解，称为内质网相关降解(ERAD)，这一过程与细胞应激的管理和许多其他医学上重要的蛋白质的调节有关。研究人员正在研究HMGR经历调节降解的保守机制，使用酵母分子生物学、生物化学和正向和反向遗传学来揭示潜在的机制。这项工作表明，泛素蛋白酶体途径是调节HMGR降解的中心，这也是哺乳动物HMGR的一种运行机制。目前的目标是通过分离和研究HRD基因(HMG co a还原酶降解)和COD基因(控制还原酶降解)来发现所有与调节降解有关的蛋白质，HRD基因编码ERAD的降解机制，COD基因编码负责将类固醇途径信号耦合到HMGR稳定性的蛋白质。目前的目标是1)分析已发现的HRD和COD基因，2)表征HMGR分子的特征，使其经历这种独特的控制模式；3)开发和开发方法来分离每个基因类别的新成员，以及4)使用这些努力得出的工具和技术在体外重建HMGR的调节降解。

HMG-CoA reductase (HMGR) is an ER resident protein required for cholesterol biosynthesis whose selective degradation occurs in a regulated manner in both mammalian cells and in yeast. Regulated degradation of HMGR allows control of the levels of this enzyme in response to changing cellular need for cholesterol pathway products. Although untapped as an axis of clinical modulation, the regulated degradation of HMGR is absolutely specific for HMGR and thus holds promise for devising new strategies for modulation. Furthermore, HMGR is degraded by a poorly-understood pathway of degradation called ER-associated degradation (ERAD), a process that is implicated in management of cellular stress and in the regulation of numerous other medically important proteins. The investigator is studying the conserved mechanisms by which HMGR undergoes regulated degradation, using yeast molecular biology, biochemistry, and forward and reverse genetics to reveal the underlying mechanisms. The work has shown that the ubiquitin proteasome pathway is central to the regulated degradation of HMGR, a mechanism in operation for mammalian HMGR as well. The current goals are to discover all the proteins responsible for regulated degradation, by the isolation and study of HRD genes (Hmg co a Reductase Degradation), that encode the degradation machinery of ERAD, and COD genes (Control Of reductase Degradation), that encode proteins responsible for the coupling of the sterol pathway signals to the stability of HMGR. Current goals are 1) the analysis of discovered HRD and COD genes, 2) characterize the features of the HMGR molecule that allow it to undergo this unique mode of control; 3) develop and exploit methods to isolate new members of each gene class, and 4) reconstitute regulated degradation of HMGR in vitro using the tools and techniques derived from these efforts.