Regulation of protein degradation and homeostasis by ubiquitylation

大多数细胞功能都是由蛋白质执行的，这使得细胞维持功能蛋白质并破坏受损蛋白质至关重要，这一过程称为蛋白质稳态。在衰老过程中，蛋白质稳定性逐渐下降，导致受损蛋白质的积累。蛋白质稳态的丧失以及错误折叠和聚集的蛋白质的积累是与年龄相关的疾病如阿尔茨海默病、亨廷顿病、帕金森病和肌萎缩性侧索硬化症（ALS）的常见促成因素。受损的蛋白质需要用称为泛素的破坏信号标记。泛素信号由蛋白酶体识别，蛋白酶体是一种大型分子机器，可以展开和降解受损蛋白。泛素信号被称为次泛素化酶（DUB）的酶家族去除，并且与这种重要的调节功能一致，突变的DUB涉及几种人类疾病。我们研究的主要目标是了解泛素如何发出降解的靶蛋白信号，以及DUBs如何调节蛋白质降解。我预计我们的研究将提供重要的见解如何调节蛋白质。对这一基本过程的更好理解将成为开发新策略以对抗神经退行性疾病的基础

The majority of cellular functions are performed by proteins, making it vital to a cell to maintain functional proteins and destroy damaged ones, a process known as proteostasis. There is a progressive decline in proteostasis during the ageing process that results in the accumulation of damaged proteins. Loss of proteostasis and accumulation of misfolded and aggregated proteins is a common contributing factor to age-related diseases such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis (ALS). Damaged proteins need to be tagged with a destruction signal called ubiquitin. The ubiquitin signals are recognized by the proteasome, a large molecular machine which unfolds and degrades the damaged proteins. Ubiquitin signals are removed by a family of enzymes called deubuiquitinating enzymes (DUBs) and in line with this important regulatory function, mutated DUBs are implicated in several human diseases. The main goals of our research are to understand how ubiquitin signals target proteins for degradation, and how protein degradation is regulated by DUBs. I anticipate that our research will provide important insights into how proteostasis is regulated. An improved understanding of this fundamental process will form the basis for the development of novel strategies to combat neurodegenerative disorders