Department of Clinical Research Center, Xuyi People's Hospital, 28 Hongwu Road, Xuyi, 211700, Jiangsu, People's Republic of China.
Cancer Chemother Pharmacol. 2018 May;81(5):797-808. doi: 10.1007/s00280-018-3541-8. Epub 2018 Feb 15.
The ubiquitin-proteasome system (UPS) is an important system that regulates the balance of intracellular proteins, and it is involved in the regulation of multiple vital biological processes. The approval of bortezomib for relapsed and refractory multiple myeloma has proven that agents targeting the UPS have the potential to be effective treatment strategies for diseases. Among of all of the components of the UPS, cullin-RING ligases (CRLs) are the focus of research. CRLs are the largest family of ubiquitin E3 ligases and they play a critical role in substrate binding. CRL activity is modulated by many pathways in which neddylation modification is the essential process for cullin activation. Thus, targeting the neddylation pathway of cullins could indirectly affect CRL activity, thereby interfering with substrate protein ubiquitination. In addition to cullin proteins, there are some other target proteins of neddylation, such as p53, mouse double minute 2, and epidermal growth factor receptor. For target proteins, neddylation modification mainly causes functions changes, not degradation. In addition, the level of neddylation is also closely related to disease development and prognosis. In this review, we summarize the research on some target proteins and active target agents of neddylation pathways, and explore the role of neddylation in disease therapy. We came to the conclusion that conducting research on neddylation may be a potential approach to discover some novel targets and agents that could be effective without serious side effects.
泛素-蛋白酶体系统（UPS）是调节细胞内蛋白质平衡的重要系统，参与调节多种重要的生物过程。硼替佐米治疗复发性和难治性多发性骨髓瘤的获批证明，靶向 UPS 的药物有可能成为治疗疾病的有效治疗策略。在 UPS 的所有成分中，Cullin-RING 连接酶（CRLs）是研究的重点。CRLs 是最大的泛素 E3 连接酶家族，它们在底物结合中起着关键作用。CRL 活性受许多途径调节，其中 neddylation 修饰是 Cullin 激活的必要过程。因此，靶向 Cullin 的 neddylation 途径可以间接影响 CRL 活性，从而干扰底物蛋白的泛素化。除了 Cullin 蛋白，还有一些其他的 neddylation 靶蛋白，如 p53、鼠双微体 2 和表皮生长因子受体。对于靶蛋白，neddylation 修饰主要导致功能变化，而不是降解。此外，neddylation 的水平也与疾病的发展和预后密切相关。在这篇综述中，我们总结了 neddylation 途径的一些靶蛋白和活性靶剂的研究，并探讨了 neddylation 在疾病治疗中的作用。我们得出结论，对 neddylation 的研究可能是发现一些新的、有效且没有严重副作用的靶标和药物的潜在方法。
