GCN5 is a required cofactor for a ubiquitin ligase that targets NF-κB/RelA
- Xicheng Mao1,2,
- Nathan Gluck1,2,
- Duo Li3,
- Gabriel N. Maine1,2,4,
- Haiying Li1,2,
- Iram W. Zaidi1,2,
- Aparna Repaka1,2,
- Marty W. Mayo3 and
- Ezra Burstein1,2,5,67
- 1Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
- 2Molecular Mechanisms of Disease Program, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;
- 3Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908, USA;
- 4Department of Clinical Pathology, William Beaumont Hospital, Royal Oak, Michigan 48073, USA;
- 5Gastroenterology Section at the Ann Arbor VA Medical Center, Ann Arbor, Michigan 48105, USA
Abstract
The transcription factor NF-κB is a critical regulator of inflammatory and cell survival signals. Proteasomal degradation of NF-κB subunits plays an important role in the termination of NF-κB activity, and at least one of the identified ubiquitin ligases is a multimeric complex containing Copper Metabolism Murr1 Domain 1 (COMMD1) and Cul2. We report here that GCN5, a histone acetyltransferase, associates with COMMD1 and other components of the ligase, promotes RelA ubiquitination, and represses κB-dependent transcription. In this role, the acetyltransferase activity of GCN5 is not required. Interestingly, GCN5 binds more avidly to RelA after phosphorylation on Ser 468, an event that is dependent on IKK activity. Consistent with this, we find that both GCN5 and the IκB Kinase (IKK) complex promote RelA degradation. Collectively, the data indicate that GCN5 participates in the ubiquitination process as an accessory factor for a ubiquitin ligase, where it provides a novel link between phosphorylation and ubiquitination.
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Footnotes
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↵6 Present address: Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Room J5.126, Dallas, TX 75390-9151, USA.
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↵7 Corresponding author.
↵E-MAIL ezra.burstein{at}utsouthwestern.edu; FAX (214) 648-2022.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1748409.
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Supplemental material is available at http://www.genesdev.org.
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- Received October 3, 2008.
- Accepted February 25, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press
