The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
Direct, Noncatalytic Mechanism of IKK Inhibition by A20
Open accessAbstract
SUMMARY A20 is a potent anti-inflammatory protein that inhibits NF-κB, and A20 dysfunction is associated with autoimmunity and B-cell lymphoma. A20 harbors a deubiquitination enzyme domain and can employ multiple mechanisms to antagonize ubiquitination upstream of NEMO, a regulatory subunit of the IκB kinase complex (IKK). However, direct evidence of IKK inhibition by A20 is lacking, and the inhibitory mechanism remains poorly understood. Here we show that A20 can directly impair IKK activation without deubiquitination or impairment of ubiquitination enzymes. We find that polyubiquitin binding by A20, which is largely dependent on A20’s seventh zinc finger motif (ZnF7), induces specific binding to NEMO. Remarkably, this ubiquitin-induced recruitment of A20 to NEMO is sufficient to block IKK phosphorylation by its upstream kinase TAK1. Our results suggest a non-catalytic mechanism of IKK inhibition by A20 and a means by which polyubiquitin chains can specify a signaling outcome.
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Cites
Deng, L., Wang, C., Spencer, E., Yang, L., Braun, A., You, J., Slaughter, C., Pickart, C., & Chen, Z. J. (2000) · Cell · doi:10.1016/s0092-8674(00)00126-4 · Cited by 1,872
Self-citationFailure to Regulate TNF-Induced NF-κB and Cell Death Responses in A20-Deficient Mice
Lee, E. G., Boone, D. L., Chai, S., Libby, S. L., Chien, M., Lodolce, J. P., & Ma, A. (2000) · Science · doi:10.1126/science.289.5488.2350 · Cited by 1,409
Self-citationSong, H. Y., Rothe, M., & Goeddel, D. V. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.13.6721 · Cited by 414
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Toll-Like Receptor Signaling Pathways
Kawasaki, T., & Kawai, T. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00461 · Cited by 3,233
Regulation of NF-κB by TNF family cytokines
Hayden, M. S., & Ghosh, S. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.05.004 · Cited by 1,115
Deubiquitylating enzymes and drug discovery: emerging opportunities
Harrigan, J. A., Jacq, X., Martin, N. M., & Jackson, S. P. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.152 · Cited by 940
A20: linking a complex regulator of ubiquitylation to immunity and human disease
Ma, A., & Malynn, B. A. (2012) · Nature Reviews Immunology · doi:10.1038/nri3313 · Cited by 548
Self-citationA20 in inflammation and autoimmunity
Catrysse, L., Vereecke, L., Beyaert, R., & van Loo, G. (2014) · Trends in Immunology · doi:10.1016/j.it.2013.10.005 · Cited by 493
Metadata
- Authors
- Skaug, B., Chen, J., Du, F., He, J., Ma, A., & Chen, Z. J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2011-11
- Volume
- 44
- Issue
- 4
- Pages
- 559-571
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2038664197
- Cited by
- 251
- References
- 3
- FWCI
- 6.97
- Type
- journal article
- Language
- en
- Open access
- bronze
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