NEDD8

Official Full Name

NEDD8 ubiquitin like modifier

Organism

Homo sapiens

GeneID

4738

Background

Enables ubiquitin protein ligase binding activity. Acts upstream of or within protein neddylation. Located in cytosol and nucleoplasm. Biomarker of Parkinson's disease and malignant astrocytoma. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

NEDD-8;

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Detailed Information

NEDD8 is one of the most important ubiquitin-like proteins. Because of its close relationship with DNA damage and apoptosis, inhibition of ubiquitination has been applied to the treatment of various diseases, especially the proliferation of various cancer cells. . Because it also regulates transcription factors and regulates dendritic cell responses, ubiquitination can also be a potential target in the treatment of various diseases such as inflammation and bacterial infection.

Figure 1. Regulation of cullin-RING ubiquitin ligase (CRL) activity by neddylation and deneddylation. (Kandala, S., et al. 2014)

The Structure and Mode of Operation of NEDD8

NEDD8 has a homology of 59% in humans, and many ubiquitinational regulation is found in many human diseases such as neurodegenerative diseases and cancer. NEDD8 binds to the target protein through an enzymatic cleavage cascade. However, the NEDD8 gene organism needs to be cleaved by a C-terminal hydrolase such as NEDP1 (NEDD8 protease 1) and UCH-L3 (ubiquitin carboxyl-terminal hydrolase L3). The Cullins family is a very important substrate for NEDD8. CRLs control many important biological processes, including tumorigenesis. NEDD8 also has many non-cullin substrates. P53 is a tumor suppressor and is strictly regulated by ubiquitination and ubiquitination. Members of the p53 family are regulated by p73 ubiquitin. The ribosome protein L11 is also considered to be a potential NEDD8 substrate. Ubiquitin-like regulation regulates the subcellular localization and stability of L11. Human antigen R (HuR) is a central RNA-binding protein that is enriched in many cancers and can be regulated by MDM2 ubiquitination; caspase is regulated by IAP, Shc ubiquitination. Histone H4 (histone 4) is regulated by RNF111 (Ring Finger Protein 111) ubiquitination. In addition, the EGFR (epidermal growth factor receptor), the transcriptional regulator HIF1α (hypoxia inducible factor 1α) /HIF2α (hypoxia inducible factor-2α) and breast cancer associated 3 (BCA3) are all regulated by ubiquitination.

NEDD8 regulates cellular biological activity, such as DNA damage, in a number of ways. NEDD8 forms a nuclear foci that colocalizes with DNA damage sites. NEDD8 is also involved in the regulation of apoptosis. Studies have found that the deubiquitinating enzyme DEN1 has a pro-apoptotic effect in Drosophila melanogaster. NEDD8 is closely related to the regulation of biological activity in many organisms. In fact, studies have shown that overexpression and abnormal activation of ubiquitination can cause the occurrence and development of many diseases such as cancer, inflammation and autoimmune diseases.

NEDD8 and Disease

Hepatic celluler cancer (HCC) is the fifth most common cancer in the world and the third leading cause of death. Studies have shown that hepatoma cell growth can be inhibited by inhibiting ubiquitination in the mTOR (mammalian target of rapamycin) pathway. HuR can be used as a potential target for the treatment of liver cancer. Due to the enrichment of post-translational modifications of NEDD8, overexpression and knockout of MDM2 can increase or decrease HuR levels, respectively. Breast cancer-associated protein 3 is involved in the transcriptional regulation of NF-κB by ubiquitination and p65 binding. Both wild-type and endogenous types can be modified by endogenous NEDD8. The feedback loop formed between E3 ubiquitin ligase S phase kinase associated protein 2 (Spp2) and β-transducin repeat-containing protein can be used as a potential target for breast cancer treatment. The JNK (c-Jun N-terminal kinase) pathway can also be used as a target for the treatment of breast cancer.

References:

Kandala, S. , Kim, I. M. , & Su, H. . (2014). Neddylation and deneddylation in cardiac biology. American Journal of Cardiovascular Disease, 4(4), 140-158.
Scott, D. , Sviderskiy, V. , Monda, J. , Lydeard, J. , Cho, S. , & Harper, J. ?. , et al. (2014). Structure of a ring e3 trapped in action reveals ligation mechanism for the ubiquitin-like protein nedd8. Cell, 157(7), 1671-1684.
Bailly, A. , Perrin, A. , Bou Malhab, L. J. , Pion, E. , Larance, M. , & Nagala, M. , et al. (2015). The nedd8 inhibitor mln4924 increases the size of the nucleolus and activates p53 through the ribosomal-mdm2 pathway. Oncogene.

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