Protein neddylation and its role in health and diseases

Abstract

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.

The CRL3 KCTD10 ubiquitin ligase–USP18 axis coordinately regulates cystine uptake and ferroptosis by modulating SLC7A11

“…Neddylation, an ubiquitylation-like posttranslational modification, is a biochemical reaction to attach NEDD8 onto the lysine residue of a substrate, which is catalyzed by NEDD8-activating enzyme (NAE/E1), NEDD8-conjugating enzyme (E2), and NEDD8 ligase (E3) ( 10 ). Cullin family proteins, the scaffold component of Cullin-RING ligase (CRL), are the best-characterized physiological substrates of neddylation ( 10 ). A typical CRL modular complex is composed of a scaffold cullin, an adaptor protein, a substrate-recognizing receptor, and a RING protein ( 10 ).…”

“…Cullin family proteins, the scaffold component of Cullin-RING ligase (CRL), are the best-characterized physiological substrates of neddylation ( 10 ). A typical CRL modular complex is composed of a scaffold cullin, an adaptor protein, a substrate-recognizing receptor, and a RING protein ( 10 ). Cullin neddylation activates CRLs, the largest family of E3 ubiquitin ligases that control many biological processes through ubiquitylation and degradation of many key signaling proteins ( 10 ).…”

“…Neddylation, which is overactivated in cancer and predictive of a poor clinical outcome ( 11 ), has been validated as a promising anticancer target ( 10 ). MLN4924, also known as pevonedistat, is the first-in-class small molecule inhibitor of NAE ( 12 ), currently in several phases I-III clinical trials for anticancer therapy as a single agent or in combination with chemo-drugs ( 10 ). Neddylation was also found to regulate various metabolic processes, including adipogenesis, lipid droplet formation, mitochondrial function, and cellular redox status ( 10 , 13 ).…”

“…MLN4924, also known as pevonedistat, is the first-in-class small molecule inhibitor of NAE ( 12 ), currently in several phases I-III clinical trials for anticancer therapy as a single agent or in combination with chemo-drugs ( 10 ). Neddylation was also found to regulate various metabolic processes, including adipogenesis, lipid droplet formation, mitochondrial function, and cellular redox status ( 10 , 13 ). Recently, we found that neddylation inactivation remarkably alters global metabolic profiling via inhibiting mitochondrial function and promoting glycolysis ( 14 ), and also induces glutamine uptake and metabolism by targeting CRL3 SPOP E3 ligase ( 15 ).…”

Mitochondrial dysfunction and immune suppression in BRAF V600E‐mutated metastatic melanoma

“…2,6 Concurrently, glutamine metabolism, crucial in BRAF-mutated melanoma, involves upregulated mitochondrial transporters that enhance glutamine conversion into essential metabolites for proliferation (Figure S2). Additionally, the neddylation pathway, which regulates protein ubiquitination and degradation, 7 enhances mitochondrial functionality and regulatory control over the cell cycle and immune responses, indicating the metabolic reprogramming characteristic of this aggressive cancer (Figure 2D).…”