Roos-Mattjus Pia, Sistonen Lea
Department of Biology, Abo Akademi University, Turku Centre for Biotechnology, Abo Akademi University & University of Turku, Turku, Finland.
Ann Med. 2004;36(4):285-95. doi: 10.1080/07853890310016324.
Regulating protein stability and turnover is a key task in the cell. Besides lysosomes, ubiquitin-mediated proteasomal degradation comprises the major proteolytic pathway in eukaryotes. Proteins destined for degradation by the proteasome are conjugated by a 'tag', a ubiquitin chain to a lysine, through an extensively regulated enzymatic cascade. The ubiquitylated proteins are subsequently targeted for degradation by the 26S proteasome, the major proteolytic machinery for ubiquitylated proteins in the cell. Ubiquitylation can be considered as another covalent post-translational modification and signal, comparable to acetylation, glycosylation, methylation, and phosphorylation. However, ubiquitylation has multiple roles in addition to targeting proteins for degradation. Depending on the number of ubiquitin moieties and the linkages made, ubiquitin also plays an important role in DNA repair, protein sorting and virus budding. Unregulated degradation of proteins, or abnormally stable proteins, interfere with several regulatory pathways, and the ubiquitin-proteasome pathway is affected in a number of diseases, such as neurodegenerative diseases, cellular atrophies and malignancies. Therefore, dissecting the ubiquitin-proteasome pathway and identifying proteins involved in conjunction with the signals required for specific degradation of certain substrates, would help in developing novel therapeutic approaches to treat diseases where the ubiquitin-proteasome pathway is impaired.
调控蛋白质稳定性和周转是细胞中的一项关键任务。除溶酶体外，泛素介导的蛋白酶体降解是真核生物中的主要蛋白水解途径。被蛋白酶体降解的蛋白质通过一个广泛调控的酶促级联反应，被一个“标签”（一条泛素链）连接到赖氨酸上。随后，泛素化的蛋白质被26S蛋白酶体靶向降解，26S蛋白酶体是细胞中泛素化蛋白质的主要蛋白水解机制。泛素化可被视为另一种共价翻译后修饰和信号，类似于乙酰化、糖基化、甲基化和磷酸化。然而，除了将蛋白质靶向降解外，泛素化还有多种作用。根据泛素部分的数量和形成的连接方式，泛素在DNA修复、蛋白质分选和病毒出芽中也起着重要作用。蛋白质的不受调控的降解或异常稳定的蛋白质会干扰多种调控途径，泛素-蛋白酶体途径在许多疾病中受到影响，如神经退行性疾病、细胞萎缩和恶性肿瘤。因此，剖析泛素-蛋白酶体途径并确定与某些底物特异性降解所需信号相关的蛋白质，将有助于开发新的治疗方法来治疗泛素-蛋白酶体途径受损的疾病。
