ER-associated protein degradation (ERAD): The machinery for recognition, retro-translocation and degradation of misfolded proteins of the ER

所有蛋白质的正确折叠对每个细胞都是必不可少的。错误折叠不仅会导致蛋白质功能的丧失，还会导致蛋白质聚集物的形成。此外，由于先前功能蛋白的这种诱导功能障碍，也可能错误地附着在功能蛋白上。蛋白质的错误折叠不仅是一个连续发生的偶然过程，而且在热、氧自由基或重金属离子等应力作用下尤为突出。突变也是蛋白质错误折叠的主要原因。因此，细胞具有非常有效的蛋白质质量控制机制。这些机制保证了错误折叠蛋白的识别和有效消除。蛋白质质量控制的缺陷导致细胞缺陷，并构成人类许多严重疾病的原因，如神经退行性疾病（阿尔茨海默病、帕金森病、克雅氏病）、糖尿病或癌症。真核细胞的所有主要细胞区室都具有蛋白质质量控制和消除机制。本文的目的是阐明内质网（分泌系统的中心细胞器）中识别和消除错误折叠蛋白的成分和机制。这些研究将使用酵母酿酒酵母来完成，酿酒酵母已被证明是一个很好的模式生物，用于阐明真核细胞的基本“管家功能”。在过去，对这种生物的研究已经在该领域取得了突破性的成果，并使酵母成为内质网相关蛋白降解领域的起搏器。

Correct folding of all proteins is essential for every cell. Misfolding does not only lead to loss of protein function but can also lead to the formation of protein aggregates. Also a mistaken attachment to functional proteins is possible by this inducing malfunction of the formerly functional protein. Misfolding of proteins is not only an accidental process which occurs continuously but is especially prominent upon application of stresses as heat, oxygen radicals or heavy metal ions. Also mutations constitute a prominent cause of protein misfolding. Therefore the cell possesses highly effective mechanisms of protein quality control. These mechanisms guarantee the recognition of misfolded proteins and their efficient elimination. Defects in protein quality control lead to cellular defects and constitute the cause of a multitude of severe diseases in man as are neurodegenerative diseases ( Alzheimer-, Parkinson-, Creutzfeldt Jakob disease), diabetes or cancer. All major cell compartments of a eukaryotic cell possess protein quality control and elimination mechanisms. It is the aim of this proposal to elucidate the components and mechanisms which recognize and eliminate the misfolded proteins of the endoplasmic reticulum, the central organelle of the secretory system. These studies will be done using the yeast Saccharomyces cerevisiae which has turned out to be an excellent model organism for elucidating the basic "housekeeping functions" of the eukaryotic cell. In the past, studies on this organism have resulted in groundbreaking results in the field and made yeast a pacemaker in the field of ER associated protein degradation.