Aaron Ciechanover ：泛素-蛋白水解系统：从机制到人类疾病与药物靶向
The ubiquitin proteolytic system: from basic mechanisms through human diseases and onto drug targeting
Aaron Ciechanover
（Cancer and Vascular Biology Research Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel）
2004年的诺贝尔化学奖获得者Aaron Ciechanover
Between the sixties and eighties, most life scientists focused their attention on studies of nucleic acids and the translation of the coded information. Protein degradation was a neglected area, considered to be a non-specifi c, dead-end process. While it was known that proteins do turn over, the large extent and high specifi city of the process - whereby distinct proteins have halflives that range from a few minutes to several days - was not appreciated. The discovery of the lysosome by Christian de Duve did not signifi cantly change this view, as it was clear that this organelle is involved mostly in the degradation of extracellular proteins, and their proteases cannot be substrate-specific. The discovery of the complex cascade of the ubiquitin pathway revolutionized the field. It is clear now that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic pathways during cell life and death, and in health and disease. With the multitude of substrates targeted, and the myriad processes involved, it is not surprising that aberrations in the pathway are implicated in the pathogenesis of many diseases, certain malignancies and neurodegeneration among them. Degradation of a protein via the ubiquitin/proteasome pathway involves two successive steps: (a) conjugation of multiple ubiquitin moieties to the substrate, and (b) degradation of the tagged protein by the downstream 26S proteasome complex. Despite intensive research, the unknown still exceeds what we currently know on intracellular protein degradation, and major key questions remain unsolved.
Among these are the modes of specific and timed recognition for the degradation of the many substrates, and the mechanisms that underlie aberrations in the system that lead to pathogenesis of diseases. The recent discovery of modifi cation by ubiquitin-like proteins along with identifi cation of “non-canonical” polyubiquitin chains that serve non-proteolytic functions, have broadened the scope of the system beyond proteolysis and set new challenges in for biologists and proteomic experts. Major challenges in the fi eld are clearly (i) identifi cation of the cellular proteins tagged by ubiquitin and ubiquitin-like proteins, (ii) identification of the downstream elements recognized by these chains, and (iii) deciphering the structure of the different ubiquitin and ubiquitin-like chains that tag the different proteins.
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