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-specific, dead-end process. While it was known that proteins do turn over, the large extent and high specificity of the process - whereby distinct proteins have half-lives that range from a few minutes to several days - was not appreciated. The discovery of the lysosome by Christian de Duve did not significantly 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.
在 60 到 80 年代之間生命科學家的研究，專注在核酸及遺傳密碼上。蛋白質的降解 (degradation) 這塊研究領域，在當時完全被忽略了。蛋白質的降解初被認為不具專一性。事實上蛋白質被製造出來後，在細胞中可存活幾分鐘到數天之久，然後再分解。如此周而復始地重覆。這現象很不幸地，在當時沒有受到重視。即便在 Christian de Duve 發現了溶體 (lysosome) 可分解細胞外的蛋白質，也無法喚醒大家的注意。直到泛素 (ubiquitin) 降解系統的發現，才革命性地改變了這個現象。現在大家很清楚地知道蛋白質在細胞中被降解是個相當複雜的過程，它精確地控制細胞的健康與生死。如果蛋白質降解的路徑出了差錯，會引發眾多的疾病，如惡性腫瘤的生成及神經的病變。
由泛素及蛋白解體 (proteasome) 來降解蛋白質的路徑有兩個主要的步驟：
1. 將數個泛素連接在待被分解的蛋白質上。
2. 再把被泛素標示的蛋白質送到蛋白解體 (proteasome) 分子內去降解。
此領域雖經漫長的研究，但我們對細胞內蛋白質的降解，所知仍極為有限。重要的問題，如受質的專一性及降解路徑錯亂時導致疾病生成之機制，仍然沒有明確的答案，尚待繼續努力。 |
