Cited by 171Ubiquitin and proteasome pathwaysProtein Degradation and InhibitorsCancer-related Molecular Pathways

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Protein neddylation and its role in health and diseases

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Zhang, Shizhen, Yu, Qing, Li, Zhijian, Zhao, Yongchao, Sun, Yi·2024·Signal Transduction and Targeted Therapy

DOI 10.1038/s41392-024-01800-9PMC PMC10995212

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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.

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Authors: Zhang, S., Yu, Q., Li, Z., Zhao, Y., & Sun, Y.
Affiliations: Second Affiliated Hospital of Zhejiang University (CN)
Chinese Academy of Sciences (CN)
First Affiliated Hospital Zhejiang University (CN)
Corresponding author: Zhao, Yongchao
Sun, Yi
ORCID: Zhang, Shizhen
Yu, Qing
Li, Zhijian
Zhao, Yongchao
Sun, Yi
Venue: Signal Transduction and Targeted Therapy
Publisher: Springer Science and Business Media LLC
Published: 2024-04-05
Volume: 9
Issue: 1
Pages: 85-85
ISSN: 2059-3635 (ISSN-L)
DOI: 10.1038/s41392-024-01800-9
PMC: PMC10995212
OpenAlex: W4393952844
Cited by: 171
References: 537
Citations by year: 2026: 78 · 2025: 74 · 2024: 19
FWCI: 6.99
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Natural Science Foundation of China (U22A20317, 82202838, 82102749, 92053117, 81972591)
Natural Science Foundation of Zhejiang Province (LD22H300003, LZ22H160003)
The National Key R&D Program of China
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: NEDD8, cullin neddylation, cullin-RING ligases, E3 ubiquitin ligase, neddylation inhibitor, cancer, metabolic disorders, neurodegenerative diseases, liver dysfunction, small molecule inhibitors
MeSH terms: Humans, Neoplasms, Protein Processing, Post-Translational, Ubiquitins, Ubiquitin-Protein Ligases, Cullin Proteins

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Protein neddylation and its role in health and diseases

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