Neddylation

Neddylation (also NEDDylation) is the process by which the ubiquitin-like protein NEDD8 is conjugated to its target proteins. This process is analogous to ubiquitination, although it relies on its own enzymes.^[1] It is an enzymatic cascade catalyzed by first UBA3 and NAE1, which form the NEDD8 activation enzyme (E1), then the NEDD8 conjugating enzyme UBE2M or UBE2F (E2), and finally the NEDD8 ligase E3, which will bind the substrate NEDD8 to the target protein. The target protein will then have its activity, localization and/or stability affected. Proteins targeted by neddylation can be largely divided into two groups: cullins and non-cullins. Cullins, when neddylated, release CAND1 from its inhibitory binding, and that leads to the activation of Cullin Ring Ligases, which in turn perform ubiquitination.

NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8) is a protein involved in the regulation of cell growth, viability and development.^[2] It is found ubiquitously throughout all tissues and cell types, and it is essential for cell fitness. It translates to a small 8kDa protein. NEDD8 has a C-terminal domain with a di-Glycine motif that allows it to bind to its target proteins. It becomes linked to the target protein via an isopeptide linkage between its carboxy-terminal glycine and the lysine of the substrate. The neddylation of the substrate then causes a structural change in the target protein. ^[3]

Neddylation is essential for human cells, but it becomes aberrant in many pathological processes, such as cancer, neurodegenerative disorders and metabolic diseases.^[4]

Neddylation is involved in the pathogenesis of Alzheimer's disease where its activation appears to drive neurons into apoptosis by initiating cell cycle reentry.^[5] Also, evidence shows that increased NEDD8 conjugation in human oral carcinoma cells led to abnormal higher degrees of proliferation. Because NEDD8 conjugation to cullin proteins plays an important role in the regulation of the cell cycle, an upregulation in conjugation causes this proliferation.^[6]

Neddylation is also involved in cancer. Higher levels of NEDD8 are found in tumor tissues compared to its normal healthy counterparts, and this is associated to worse prognosis and advanced stages in many cancer types.^[7] Due to the clear correlation between abnormal neddylation and cancer, a neddylation inhibitor was developed. Pevonedistat or MLN4929 is the first neddylation E1 inhibitor being tested for several clinical trials in cancer patients, both as a monotherapy and in combination with other therapies.

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