Activation of the IκB Kinase Complex by TRAF6 Requires a Dimeric Ubiquitin-Conjugating Enzyme Complex and a Unique Polyubiquitin Chain
Open accessAbstract
TRAF6 is a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. We have purified a heterodimeric protein complex that links TRAF6 to IKK activation. Peptide mass fingerprinting analysis reveals that this complex is composed of the ubiquitin conjugating enzyme Ubc13 and the Ubc-like protein Uev1A. We find that TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin. Blockade of this polyubiquitin chain synthesis, but not inhibition of the proteasome, prevents the activation of IKK by TRAF6. These results unveil a new regulatory function for ubiquitin, in which IKK is activated through the assembly of K63-linked polyubiquitin chains.
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A mutant ubiquitin K63R completely abolishes UBC13/UEV1a-mediated ubiquitin chain formation independently of the RING domain.
“a mutant ubiquitin in which lysine 63 is replaced by an arginine (K63R) completely abolished UBC13/ UEV1a-mediated ubiquitin chain formation independently of the RING domain (19,20) (Fig. 4A).”
From Distinct Functional Domains Contribute to Degradation of the Low Density Lipoprotein Receptor (LDLR) by the E3 Ubiquitin Ligase Inducible Degrader of the LDLR (IDOL) (2011) · cites this paper as [19]
The Results report that ubiquitin with lysine 63 replaced by arginine (R63) abolished ubiquitin’s ability to stimulate IKK activation. They do not show that this mutant completely abolished Ubc13/Uev1A-mediated chain formation independently of the RING domain. Instead, the Results and Discussion say that TRAF6-facilitated chain assembly requires an intact RING domain. (LLM, conf=0.84)
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- Authors
- Deng, L., Wang, C., Spencer, E., Yang, L., Braun, A., You, J., Slaughter, C., Pickart, C., & Chen, Z. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Johns Hopkins University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Chen, Zhijian J
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 103
- Issue
- 2
- Pages
- 351-361
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2037454778
- Cited by
- 1,872
- References
- 0
- Citations by year
- 2026: 38 · 2025: 49 · 2024: 41 · 2023: 40 · 2022: 78 · 2021: 52 · 2020: 62 · 2019: 61 · 2018: 74 · 2017: 81 · 2016: 64 · 2015: 66 · 2014: 86 · 2013: 77 · 2012: 85
- FWCI
- 22.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM59203, GM60372, R01GM059203, R01GM060372)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- TRAF6, IκB kinase, NF-κB signaling, Ubc13, RING domain, IKK activation, ubiquitin signaling, inflammatory cytokines
- MeSH terms
- Amino Acid Sequence, Biopolymers, Cell-Free System, Cloning, Molecular, Enzyme Activation, HeLa Cells, Humans, Ligases, Molecular Sequence Data, Peptide Mapping, Proteins, Transcription Factors, Ubiquitins, Protein Serine-Threonine Kinases, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Dimerization, Polyubiquitin, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, TNF Receptor-Associated Factor 6, I-kappa B Kinase
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