自噬相关去泛素化酶及其小分子抑制剂的研究进展

自噬是进化上高度保守并受到多途径严密调控的细胞生物学过程,其向溶酶体递送多种细胞质组分以进行细胞内物质的降解以及再循环.这一过程涉及到细胞器的更新、错误折叠蛋白质和蛋白质聚集体以及细胞内病原体的清除.因此,自噬对于细胞稳态的维持至关重要,与许多人类疾病的发生发展密切相关.随着细胞自噬调节机制研究的不断深入,越来越多的去泛素化酶被证明在自噬相关的泛素信号调控系统中发挥了重要的作用.这些去泛素化酶作用于细胞自噬的不同阶段,靶向调节不同的泛素化自噬功能元件或自噬底物.去泛素化酶作为包括神经退行性疾病以及肿瘤在内的细胞自噬相关疾病的治疗靶点受到了广泛的关注,其中各类小分子抑制剂的发现为进一步研究去泛素化酶的自噬调节活性及相关疾病的治疗提供了可能.

Research Progress of Autophagy-related Deubiquitinating Enzymes and Their Small-molecule Inhibitors

Autophagy is an evolutionary conserved cellular process that delivers the intracellular components to lysosome for degradation and recycling, which is tightly regulated by multiple pathways. This catabolic process involves the renewal of organelles, the removal of misfolded proteins and protein aggregates as well as the elimination of pathogens in cells. Therefore, autophagy is critical to maintain cellular homeostasis and closely related to the development of many human diseases. With the deepening of the mechanism research of autophagy regulation, more and more deubiquitinating enzymes have been proved to play an important role in autophagy-related ubiquitin signaling system. These enzymes can act at different stages of autophagy, and target different ubiquitinated machinery components or substrates of autophagy. As the therapeutic targets for autophagy-related diseases including neurodegeneration diseases and tumors, deubiquitinating enzymes have attracted extensive attention. The discovery of various small-molecule inhibitors provides the possibility to further study the autophagy regulatory activity of the ubiquitinases and also the treatment of related diseases.