negative regulation of protein neddylation

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of protein neddylation. [GOC:obol]

Negative regulation of protein neddylation is a crucial cellular process that controls the activity of a wide range of proteins involved in diverse cellular functions. Neddylation is the covalent attachment of the ubiquitin-like protein NEDD8 (Neural precursor cell expressed, developmentally downregulated 8) to a lysine residue on target proteins, often referred to as neddylation substrates. This modification can alter the protein's stability, localization, and activity, thereby influencing its biological function.

Negative regulation of neddylation ensures that this process is tightly controlled and does not become overactive, potentially disrupting cellular homeostasis. Several mechanisms contribute to negative regulation of protein neddylation:

**1. Inhibition of NEDD8 E1 Activating Enzyme (NAE):**
NAE is responsible for activating NEDD8, the first step in the neddylation cascade. NAE inhibition prevents the activation of NEDD8 and subsequently blocks the entire neddylation process.

**2. Inhibition of NEDD8 E2 Conjugating Enzyme (UBE2F):**
UBE2F acts as a molecular shuttle, transferring activated NEDD8 from NAE to the NEDD8 E3 ligase, facilitating the final step of the neddylation reaction. Inhibiting UBE2F prevents the transfer of NEDD8 to target proteins.

**3. Activation of NEDD8-Specific Deubiquitinases (NEDD8 DUBs):**
NEDD8 DUBs act as 'de-neddylases', removing NEDD8 from neddylated proteins. This process is crucial for regulating the duration of neddylation and ensuring that neddylation is reversible.

**4. Inhibition of NEDD8 E3 Ligases:**
NEDD8 E3 ligases are responsible for recognizing and binding to specific neddylation substrates, facilitating the transfer of NEDD8 to the substrate. Inhibiting the activity of these ligases prevents the neddylation of specific target proteins.

**5. Competition with NEDD8:**
Some proteins can compete with NEDD8 for binding to the NEDD8 E3 ligases, effectively blocking NEDD8 binding and preventing neddylation.

**6. Degradation of NEDD8:**
NEDD8 itself can be degraded through proteasomal or lysosomal pathways, reducing the availability of NEDD8 for neddylation.

**7. Inhibition of NAE expression:**
Downregulation of NAE expression reduces the overall levels of the enzyme, thereby limiting the rate of NEDD8 activation and subsequent neddylation.

**Overall, the negative regulation of protein neddylation is a complex and dynamic process involving multiple mechanisms. By controlling the levels of neddylation, cells maintain cellular homeostasis and ensure proper regulation of protein activity in various cellular functions, including cell cycle control, DNA repair, and signal transduction.'
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Proteins (2)

Compounds (2)