Novel proteases with deubiquitylation activity: examination of function in T lymphocytes

过去25年的工作已经确立了调节蛋白质泛素化在广泛的细胞功能中的重要性，包括细胞周期控制，转录调节和细胞信号传导。这些过程在许多人类疾病如癌症、神经变性和免疫紊乱中受到干扰。到目前为止，大多数分析集中在控制泛素连接的机制。然而，广泛的类去泛素化酶（DUBs）的认识强烈建议DUBs的监管（而不是纯粹的回收）的作用。因此，预计对一类酶的计划分析将阐明细胞生理学的重要和医学相关方面。最近已经鉴定了一类新的含有卵巢肿瘤结构域（OTU）的这些酶，该结构域编码推定的泛素特异性半胱氨酸蛋白酶。这个结构域在整个进化过程中是保守的。Obubain 1（OTUB 1）是该蛋白家族的成员，不参与大部分胞质蛋白的去泛素化。初步证据表明，OTUB 1在调节T淋巴细胞的抗原反应性中发挥特异性作用。对这一过程的深入了解可能对我们理解免疫调节具有重要意义，并可能将含有OTU的蛋白质鉴定为新的治疗靶点。

Work over the last 25 years has established the importance of regulating protein ubiquitylation in a wide range of cellular functions including cell cycle control, transcriptional regulation, and cell signaling. These processes are disturbed in many human diseases such as cancer, neurodegeneration and immunological disorders. So far, most analyses have focused on mechanisms controlling ubiquitin ligation. However, the recognition of extensive classes of deubiquitylating enzymes (DUBs) strongly suggests a regulatory (as opposed to purely recycling) role for DUBs. Thus it is anticipated that the planned analysis of one class of these enzymes would shed light on important and medically relevant aspects of cellular physiology. A novel class of these enzymes containing an ovarian tumor domain (OTU), which encodes for a putative ubiquitin-specific cysteine protease, has been recently identified. This domain is conserved throughout evolution. Obubain 1 (OTUB1), a member of this protein family, does not contribute to the deubiquitylation of the bulk of cytosolic proteins. Preliminary evidence suggests that OTUB1 plays a specific role in the regulation of antigen responsiveness of T lymphocytes. Insights into this process could have important implications for our understanding of immune-modulation, and may identify OTU containing proteins as novel therapeutic targets.