Studies on proteolysis mediated by the proteasomes and ubiquitin

蛋白酶体（一种真核生物的ATP依赖性蛋白酶复合物）是一种复杂的细胞装置，能够选择性地粉碎由泛素（一种翻译后修饰物，为蛋白水解提供目的信号）修饰的不必要的蛋白质。它通过快速、有序、彻底和单向地催化生物反应，在控制各种细胞活动中发挥核心作用。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）在生命科学领域的不同作用。在本课题“蛋白酶体和泛素介导的蛋白质水解研究”中，我们对蛋白酶体的主要研究内容是：（1）分析哺乳动物蛋白酶体的三级结构，（2）阐明蛋白酶体的组装机制，重点是新发现的PAC（3）新的蛋白酶体激活剂家族蛋白PA 28 α、PA 28 β和PA 28 γ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的质量控制泛素蛋白连接酶（E3）：CHIP是一种分子伴侣依赖性E3，Parkin由吃自己的致病基因编码”）和两种新的泛素样（UBL）修饰系统，如NEDD 8和Ufml通路，通过产生各种相关基因受损的模型小鼠。近年来，在21世纪的老龄化社会中，各种疾病，如癌症、传染病和神经变性疾病，一直在增加。考虑到这种情况，它已被澄清，作为一个中心的情况下，UPS的功能失调导致这些棘手的疾病。因此，我们的研究可能有助于新的生物科学领域的发展，以及对难治性疾病的治疗。

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.