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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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Fig. 1 The neddylation pathway. a Three enzymes catalyze the NEDD8 attachment to a substrate: E1 activation enzyme, a heterodimer of catalytic subunit UBA3/NAEβ, and regulatory subunit NAE1/APPBP1; E2 conjugation enzymes, UBE2M/UBC12 and UBE2F; and E3 ligases (e.g., RBX1 and RBX2). One type of enzyme that removes NEDD8 from a substrate: Deneddylase (e.g CNS5). b Neddylation reaction with the UBE2M-RBX1 pair to catalyze neddylation of CULs 1-4, and UBE2M-other E3s pairs for neddylation of non-cullin substrates, and the UBE2F-RBX2 pair to catalyze CUL5 neddylation. c Classification of known non-cullin substrates
Fig. 1 The neddylation pathway. a Three enzymes catalyze the NEDD8 attachment to a substrate: E1 activation enzyme, a heterodimer of catalytic subunit UBA3/NAEβ, and regulatory subunit NAE1/APPBP1; E2 conjugation enzymes, UBE2M/UBC12 and UBE2F; and E3 ligases (e.g., RBX1 and RBX2). One type of enzyme that removes NEDD8 from a substrate: Deneddylase (e.g CNS5). b Neddylation reaction with the UBE2M-RBX1 pair to catalyze neddylation of CULs 1-4, and UBE2M-other E3s pairs for neddylation of non-cullin substrates, and the UBE2F-RBX2 pair to catalyze CUL5 neddylation. c Classification of known non-cullin substratesCC BY · PubMed Central
Fig. 2 The chronicles of neddylation-related research. Timeline showing important discovery events in the field of neddylation research over past 30 years: From the cloning of NEDD8, demonstration of NEDD8 conjugates to cullins, identification of neddylation E1 and E2s, revelation of neddylation E2/E3 crystal structures, to discovery of neddylation E1 inhibitor (MLN4924/Pevonedistat) and its clinical trials, and its FDA approval for the treatment of MDS
Fig. 2 The chronicles of neddylation-related research. Timeline showing important discovery events in the field of neddylation research over past 30 years: From the cloning of NEDD8, demonstration of NEDD8 conjugates to cullins, identification of neddylation E1 and E2s, revelation of neddylation E2/E3 crystal structures, to discovery of neddylation E1 inhibitor (MLN4924/Pevonedistat) and its clinical trials, and its FDA approval for the treatment of MDSCC BY · PubMed Central
Fig. 3 The crystal structures of neddylation enzymes in complex with cullin substrates. a The model derived from the co-crystal structure of RBX1-UBE2M ~ NEDD8-CUL1CTD-DCN1P revealed how neddylation induces a conformational change to bring the E2 close to the substrate (modified based on the reported structure96). b The crystal structure of a neddylated CRL1β-TRCP-UBE2D~Ub-substrate intermediate revealed how NEDD8 acts as a nexus between cullin elements and the RING-activated ubiquitin-linked E2 to promote substrate ubiquitylation (PDB ID: 6TTU). c Co-crystal structure of CUL5-ARIH2 E3-E3 ubiquitin ligase unveiled the unique role of NEDD8 in promoting interactions of CUL5-RBX2 with a RING-between-RING (RBR) E3, ARIH2 (PDB ID: 7ONI). d An alignment of the reported structures of CRL1β-TRCP, SAG-CUL5, and CRL7FBXW8 (PDB ID: 6TTU, 6V9I and 7Z8B) shows the different CRL structures with the reported neddylation site. A model of CRL7 in complex with neddylated CRL1 illustrates a unique CRL-CRL interaction that enhances substrate ubiquitylation. e The Electron microscopy structure of CAND1-CUL1-RBX1-SKP1-SKP2-CKS1-CDK2 complex (PDB ID: 8OR0). f The Electron microscopy structure of NEDD8-CUL2-RBX1-ELOB-ELOC-VHL-CSN (PDB ID: 6R7F). All protein structures were illustrated by PyMol software (The PyMol Molecular Graphics System, Version 2.6.0a0 Open-Source, Schrödinger, LLC)
Fig. 3 The crystal structures of neddylation enzymes in complex with cullin substrates. a The model derived from the co-crystal structure of RBX1-UBE2M ~ NEDD8-CUL1CTD-DCN1P revealed how neddylation induces a conformational change to bring the E2 close to the substrate (modified based on the reported structure96). b The crystal structure of a neddylated CRL1β-TRCP-UBE2D~Ub-substrate intermediate revealed how NEDD8 acts as a nexus between cullin elements and the RING-activated ubiquitin-linked E2 to promote substrate ubiquitylation (PDB ID: 6TTU). c Co-crystal structure of CUL5-ARIH2 E3-E3 ubiquitin ligase unveiled the unique role of NEDD8 in promoting interactions of CUL5-RBX2 with a RING-between-RING (RBR) E3, ARIH2 (PDB ID: 7ONI). d An alignment of the reported structures of CRL1β-TRCP, SAG-CUL5, and CRL7FBXW8 (PDB ID: 6TTU, 6V9I and 7Z8B) shows the different CRL structures with the reported neddylation site. A model of CRL7 in complex with neddylated CRL1 illustrates a unique CRL-CRL interaction that enhances substrate ubiquitylation. e The Electron microscopy structure of CAND1-CUL1-RBX1-SKP1-SKP2-CKS1-CDK2 complex (PDB ID: 8OR0). f The Electron microscopy structure of NEDD8-CUL2-RBX1-ELOB-ELOC-VHL-CSN (PDB ID: 6R7F). All protein structures were illustrated by PyMol software (The PyMol Molecular Graphics System, Version 2.6.0a0 Open-Source, Schrödinger, LLC)CC BY · PubMed Central
Fig. 4 Neddylation regulation of several key biological processes via NEDD8 attachment to various substrates. By attachment of NEDD8 to its cullin and non-cullin substrates, neddylation regulates various key biological processes, including signaling transduction and epigenetic regulation, cellular stress and immune responses, cell growth and organ development, stem cell maintenance, mitochondria function and energy metabolism. Created at BioRender.com
Fig. 4 Neddylation regulation of several key biological processes via NEDD8 attachment to various substrates. By attachment of NEDD8 to its cullin and non-cullin substrates, neddylation regulates various key biological processes, including signaling transduction and epigenetic regulation, cellular stress and immune responses, cell growth and organ development, stem cell maintenance, mitochondria function and energy metabolism. Created at BioRender.comCC BY · PubMed Central
Fig. 5 Abnormal neddylation in human diseases. Dysregulation of neddylation or de-neddylation pathways is associated with several human diseases, such as metabolic disorders, liver dysfunction, neurodegenerative disorders, cardiac diseases and immune-related inflammatory and infectious diseases
Fig. 5 Abnormal neddylation in human diseases. Dysregulation of neddylation or de-neddylation pathways is associated with several human diseases, such as metabolic disorders, liver dysfunction, neurodegenerative disorders, cardiac diseases and immune-related inflammatory and infectious diseasesCC BY · PubMed Central
Fig. 6 Abnormal neddylation in cancers. Neddylation pathway is hyper-activated in many types of human cancers, and overexpression of some neddylation components is associated with advanced stages of diseases and poor survival of cancer patients. Created at BioRender.com
Fig. 6 Abnormal neddylation in cancers. Neddylation pathway is hyper-activated in many types of human cancers, and overexpression of some neddylation components is associated with advanced stages of diseases and poor survival of cancer patients. Created at BioRender.comCC BY · PubMed Central
Fig. 7 Small molecular inhibitors targeting neddylation pathway. a E1 inhibitor, represented by MLN4924. b UBE2F E2 inhibitor HA-9104. c Several inhibitors that disrupt the UBE2M-DCN1 binding (PDB ID: 3TDU), represented by NAcM-OPT, compound 40, DI-591 and DI-1895. d Non-specific E3 inhibitor of gossypol targeting CUL1-RBX1 and CUL5-RBX2. Created at BioRender.com
Fig. 7 Small molecular inhibitors targeting neddylation pathway. a E1 inhibitor, represented by MLN4924. b UBE2F E2 inhibitor HA-9104. c Several inhibitors that disrupt the UBE2M-DCN1 binding (PDB ID: 3TDU), represented by NAcM-OPT, compound 40, DI-591 and DI-1895. d Non-specific E3 inhibitor of gossypol targeting CUL1-RBX1 and CUL5-RBX2. Created at BioRender.comCC BY · PubMed Central
Fig. 8 Future perspectives. A total of nine research directions are proposed for future investigations, covering from basic mechanistic study, target identification and validation, the use of animal disease models to eventually discover specific neddylation inhibitors for clinical trials to treat various human diseases with abnormal activation of the neddylation pathway (see text for details). Created at BioRender.com
Fig. 8 Future perspectives. A total of nine research directions are proposed for future investigations, covering from basic mechanistic study, target identification and validation, the use of animal disease models to eventually discover specific neddylation inhibitors for clinical trials to treat various human diseases with abnormal activation of the neddylation pathway (see text for details). Created at BioRender.comCC BY · PubMed Central

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Metadata

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
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
Licence
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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