Studies on proteolysis mediated by the proteasomes and ubiquitin

蛋白酶体(一种真核细胞中依赖于ATP的蛋白酶复合体)是一种复杂的细胞装置，能够选择性地粉碎被泛素修饰的不必要的蛋白质。泛素是一种翻译后修饰的修饰物，为蛋白质降解提供目的信号。它通过快速、有序、彻底和单向地催化生物反应，在控制一系列不同的细胞活动方面发挥着核心作用。在过去的25年里，我们一直致力于全面阐明泛素-蛋白酶体系统(UPS)在生命科学领域中的不同作用。在“蛋白酶体和泛素介导的蛋白降解研究”项目中，我们对蛋白酶体的研究主要集中在：(1)哺乳动物蛋白酶体作为一个异常大的多蛋白复合体的三级结构的分析；(2)组装机制的阐明，重点是新发现的蛋白酶体组装伴侣1/2异二聚体复合体和热休克蛋白90；(3)新的蛋白酶体激活蛋白家族蛋白28α、PA28β和PA28γ的免疫遗传学分析。在泛素项目中，我们感兴趣的是分析细胞中质量控制的泛素蛋白连接酶(E3S)：CHIP是一个依赖分子伴侣的E3，Parkin是由自食其食的致病基因编码的)，以及两个新的泛素样蛋白(UBL)修饰系统，如NEDD8和UFML通路，通过各种相关基因受损的模型鼠的世代。近年来，在21世纪的老龄化社会中，各种疾病如癌症、传染病、神经退行性疾病等呈上升趋势。考虑到这些情况，作为一个核心情景，UPS的故障导致了这些疑难疾病。因此，我们的研究可能有助于新的生物科学领域的发展，以及对顽固性疾病的治疗。

The proteasome (a eukaryotic ATP-dependent protease complex) is a sophisticated cellular apparatus capable of shredding unnecessary proteins modified by ubiquitin (a posttranslational modifier serving a destination signal for proteolysis) selectively. It plays a central role in the control of a diverse array of cellular activities by catalyzing biological reactions rapidly, orderly, exhaustively, and uni-directionally. Over the past 25 years, we have been aiming to elucidate comprehensively the divergent roles of the ubiquitin-proteasome system (UPS) in the life science field. In the present project named "Studies on proteolysis mediated by the proteasomes and ubiquitin", our research projects on the proteasomes were (1) the analysis of the tertiary structure of the mammalian proteasome as a unusually large multi-protein complex, (2) the clarification of assembling mechanisms, focusing on the newly-discovered PAC (proteasome assembling chaperone) 1/2 heterodimeric complex and Hsp90, and (3) immunogenetic analysis of the new proteasome activator family proteins of PA28α, PA28β and PA28γ. In the ubiquitin project, we were interested in analyzing the quality-control ubiquitin-protein ligases (E3s) in cells: CHIP is a molecular chaperone-dependent E3, Parkin is encoded by the causative gene of eating of oneself") and two novel ubiquitin-like (UBL) modifying systems, such as NEDD8 and Ufml pathways, by generation of model mice with impairment of various related genes. Recently, various diseases, such as cancers, infectious diseases, and neurodegenerative diseases, have been increasing in the aged society of the 21st century. Considering such circumstances, it has been clarified, as a central scenario, that dysfunctioning of UPS causes these intractable diseases. Thus, our studies may contribute to the development of new bio-science field as well as to that of therapies for intractable diseases.