Nedd8 Modification of Cul-1 Activates SCFβTrCP-Dependent Ubiquitination of IκBα
Open accessAbstract
Regulation of NF-kappaB occurs through phosphorylation-dependent ubiquitination of IkappaBalpha, which is degraded by the 26S proteasome. Recent studies have shown that ubiquitination of IkappaBalpha is carried out by a ubiquitin-ligase enzyme complex called SCF(beta(TrCP)). Here we show that Nedd8 modification of the Cul-1 component of SCF(beta(TrCP)) is important for function of SCF(beta(TrCP)) in ubiquitination of IkappaBalpha. In cells, Nedd8-conjugated Cul-1 was complexed with two substrates of SCF(beta(TrCP)), phosphorylated IkappaBalpha and beta-catenin, indicating that Nedd8-Cul-1 conjugates are part of SCF(beta(TrCP)) in vivo. Although only a minute fraction of total cellular Cul-1 is modified by Nedd8, the Cul-1 associated with ectopically expressed betaTrCP was highly enriched for the Nedd8-conjugated form. Moreover, optimal ubiquitination of IkappaBalpha required Nedd8 and the Nedd8-conjugating enzyme, Ubc12. The site of Nedd8 ligation to Cul-1 is essential, as SCF(beta(TrCP)) containing a K720R mutant of Cul-1 only weakly supported IkappaBalpha ubiquitination compared to SCF(beta(TrCP)) containing WT Cul-1, suggesting that the Nedd8 ligation of Cul-1 affects the ubiquitination activity of SCF(beta(TrCP)). These observations provide a functional link between the highly related ubiquitin and Nedd8 pathways of protein modification and show how they operate together to selectively target the signal-dependent degradation of IkappaBalpha.
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NEDD8 uniquely activates CRL-dependent ubiquitylation despite approximately 60% identity to UB.
“Despite ≈60% identity to UB, NEDD8 uniquely activates CRL-dependent ubiquitylation2.”
From NEDD8 nucleates a multivalent cullin–RING–UBE2D ubiquitin ligation assembly (2020) · cites this paper as [2]
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References 67 · Cited by 363
- Authors
- Read, M. A., Brownell, J. E., Gladysheva, T. B., Hottelet, M., Parent, L. A., Coggins, M. B., Pierce, J. W., Podust, V. N., Luo, R.-S., Chau, V., & Palombella, V. J.
- Affiliations
- LeukoSite, Inc., Cambridge, Massachusetts 02139
- Vanderbilt University (US)
- Corresponding author
- Read, Margaret A.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2000-04-01
- Volume
- 20
- Issue
- 7
- Pages
- 2326-2333
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC85397
- OpenAlex
- W1769736739
- Cited by
- 363
- References
- 67
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 6 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 13 · 2019: 7 · 2018: 5 · 2017: 8 · 2016: 8 · 2015: 16 · 2014: 19 · 2013: 14 · 2012: 17
- FWCI
- 10.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (7r01gm053136-06)
- National Institute of General Medical Sciences (GM53136)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- NF-κB regulation, Ubc12, β-catenin, protein degradation, E3 ubiquitin ligase
- MeSH terms
- NEDD8 Protein, Amino Acid Sequence, Cell Line, Cytoskeletal Proteins, DNA-Binding Proteins, Humans, Kinetics, Molecular Sequence Data, Multienzyme Complexes, Peptide Synthases, Phosphorylation, Transfection, Ubiquitins, Trans-Activators, Helminth Proteins, Sequence Alignment, Cell Cycle Proteins, GTP-Binding Proteins, I-kappa B Proteins, Saccharomyces cerevisiae Proteins, Cullin Proteins, SKP Cullin F-Box Protein Ligases, beta-Transducin Repeat-Containing Proteins, beta Catenin
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