Neddylation is a fundamental biological process, representing a type of post-translational modification. This widespread modification plays a significant role in various cellular functions across eukaryotic organisms.
The Basics of Neddylation
Neddylation involves the covalent attachment of a small protein called NEDD8 to a target protein. NEDD8, or Neural precursor cell expressed developmentally downregulated protein 8, is classified as a ubiquitin-like protein (UBL) due to its structural resemblance to ubiquitin. This attachment occurs through a multi-step enzymatic cascade, similar to ubiquitination.
This cascade begins with an activating enzyme (E1), which uses ATP to activate NEDD8 and form a thioester linkage. The activated NEDD8 is then transferred to a conjugating enzyme (E2). Finally, a ligase enzyme (E3) facilitates the transfer of NEDD8 from the E2 enzyme to a specific lysine residue on the target protein, creating an isopeptide bond. This attachment can alter the target protein’s stability, subcellular location, and activity.
How Neddylation Regulates Cell Processes
The primary cellular function of neddylation is activating Cullin-RING Ligases (CRLs). These CRLs constitute a major class of E3 ubiquitin ligases, enzymes that attach ubiquitin to target proteins. Neddylation of cullin proteins, core components of CRLs, enhances their enzymatic activity.
This activation leads to the ubiquitination and degradation of specific target proteins by the proteasome, a protein-recycling machinery. Neddylation’s regulation of CRLs is involved in various cellular processes. These include cell cycle progression and DNA damage repair. Additionally, neddylation modulates immune responses.
Neddylation and Human Health
Dysregulated neddylation can contribute to the development and progression of various human diseases. Its involvement in cell cycle control and protein stability makes it relevant in cancer. Higher levels of NEDD8 are observed in tumor tissues compared to healthy counterparts, correlating with a worse prognosis and advanced disease stages in many cancer types.
Beyond cancer, neddylation dysregulation also plays a role in neurodegenerative disorders, such as Alzheimer’s disease, where increased NEDD8 conjugation can lead to neuronal cell death. Due to its implications in disease, targeting neddylation has emerged as a therapeutic strategy. Pevonedistat (MLN4924) is a neddylation E1 inhibitor under investigation for treating various cancers. This inhibitor blocks the neddylation pathway, preventing CRL activation and leading to the accumulation of their target proteins, which can halt cancer cell proliferation.