NEDD8 (Neural precursor cell expressed developmentally downregulated protein 8) is an ubiquitin-like protein that is covalently attached to a lysine residue of a protein substrate through a process known as neddylation, catalyzed by the enzyme cascade, namely NEDD8 activating enzyme (E1), NEDD8 conjugating enzyme (E2), and NEDD8 ligase (E3). The substrates of neddylation are categorized into cullins and non-cullin proteins. Neddylation of cullins activates CRLs (cullin RING ligases), the largest family of E3 ligases, whereas neddylation of non-cullin substrates alters their stability and activity, as well as subcellular localization. Significantly, the neddylation pathway and/or many neddylation substrates are abnormally activated or over-expressed in various human diseases, such as metabolic disorders, liver dysfunction, neurodegenerative disorders, and cancers, among others. Thus, targeting neddylation becomes an attractive strategy for the treatment of these diseases. In this review, we first provide a general introduction on the neddylation cascade, its biochemical process and regulation, and the crystal structures of neddylation enzymes in complex with cullin substrates; then discuss how neddylation governs various key biological processes via the modification of cullins and non-cullin substrates. We further review the literature data on dysregulated neddylation in several human diseases, particularly cancer, followed by an outline of current efforts in the discovery of small molecule inhibitors of neddylation as a promising therapeutic approach. Finally, few perspectives were proposed for extensive future investigations.

NEDD8（神经前体细胞表达发育下调蛋白 8）是一种类泛素蛋白，通过称为 neddylation 的过程共价连接到蛋白质底物的赖氨酸残基上，由酶级联（即 NEDD8 激活酶 (E1)）催化， NEDD8 结合酶 (E2) 和 NEDD8 连接酶 (E3)。 neddylation 的底物分为 cullin 蛋白和非 cullin 蛋白。 cullin 的 Neddy 化会激活 E3 连接酶最大家族 CRL（cullin RING 连接酶），而非 cullin 底物的 neddy 化会改变其稳定性和活性以及亚细胞定位。值得注意的是，neddylation途径和/或许多neddylation底物在各种人类疾病中异常激活或过度表达，例如代谢紊乱、肝功能障碍、神经退行性疾病和癌症等。因此，靶向neddylation成为治疗这些疾病的一种有吸引力的策略。在这篇综述中，我们首先对neddylation级联、其生化过程和调控以及与cullin底物复合的neddylation酶的晶体结构进行了概述；然后讨论neddylation如何通过对cullin和非cullin底物的修饰来控制各种关键的生物过程。我们进一步回顾了几种人类疾病（特别是癌症）中 neddylation 失调的文献数据，随后概述了目前在发现 neddylation 小分子抑制剂作为一种有前途的治疗方法方面所做的努力。最后，为未来的广泛调查提出了一些观点。