Targeting the neddylation pathway in cells as a potential therapeutic approach for diseases.

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.