Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
School of Neurobiology, Biochemistry and Biophysics, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
Trends Biochem Sci. 2019 Oct;44(10):872-884. doi: 10.1016/j.tibs.2019.04.007. Epub 2019 May 9.
Mutant protein aggregation and misfolding is often correlated with toxicity in neurodegenerative diseases. Aggregate-prone proteins are tagged by ubiquitin that signals them for destruction by the proteasome or autophagy, two key pathways for protein degradation and proteostasis. Here, we review recent studies showing that the regulation of aggregate-prone proteins by ubiquitin signaling is more complex than initially postulated. We discuss how the ubiquitin code of aggregate-prone proteins is written by specific E3 ubiquitin ligases and edited by deubiquitylating enzymes (DUBs) in cells and in brain tissues, as well as how this affects protein degradation. These studies have advanced our understanding of the specificity of the ubiquitin system and provide new information about its relevance to neurodegenerative diseases and therapy.
突变蛋白的聚集和错误折叠通常与神经退行性疾病中的毒性有关。泛素标记易聚集的蛋白质，将其标记为通过蛋白酶体或自噬进行破坏的信号，这两种途径是蛋白质降解和蛋白稳定的关键途径。在这里，我们回顾了最近的研究，这些研究表明，泛素信号对易聚集蛋白的调节比最初假设的更为复杂。我们讨论了易聚集蛋白的泛素密码如何在细胞和脑组织中由特定的 E3 泛素连接酶编写，并由去泛素化酶 (DUB) 编辑，以及这如何影响蛋白质降解。这些研究提高了我们对泛素系统特异性的理解，并提供了有关其与神经退行性疾病和治疗相关性的新信息。
