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Molecular and Cellular Biology, November 2007, p. 7451-7461, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.01101-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

IB Kinase ß Phosphorylates the K63 Deubiquitinase A20 To Cause Feedback Inhibition of the NF-B Pathway

Jessica E. Hutti,^1,2 Benjamin E. Turk,³ John M. Asara,⁴ Averil Ma,⁵ Lewis C. Cantley,^1,2 and Derek W. Abbott^6*

Department of Systems Biology, Harvard Medical School, Boston, Massachusetts,¹ Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts,² Department of Pharmacology, Yale University, New Haven, Connecticut,³ Mass Spectrometry Core Facility, Beth Israel Deaconess Medical Center, Boston, Massachusetts,⁴ Department of Medicine, University of California, San Francisco, San Francisco, California,⁵ Department of Pathology, Case Western Reserve University, Cleveland, Ohio⁶

Received 21 June 2007/ Returned for modification 13 July 2007/ Accepted 10 August 2007

Misregulation of NF-B signaling leads to infectious, inflammatory, or autoimmune disorders. IB kinase ß (IKKß) is an essential activator of NF-B and is known to phosphorylate the NF-B inhibitor, IB, allowing it to undergo ubiquitin-mediated proteasomal degradation. However, beyond IB, few additional IKKß substrates have been identified. Here we utilize a peptide library and bioinformatic approach to predict likely substrates of IKKß. This approach predicted Ser381 of the K63 deubiquitinase A20 as a likely site of IKKß phosphorylation. While A20 is a known negative regulator of innate immune signaling pathways, the mechanisms regulating the activity of A20 are poorly understood. We show that IKKß phosphorylates A20 in vitro and in vivo at serine 381, and we further show that this phosphorylation event increases the ability of A20 to inhibit the NF-B signaling pathway. Phosphorylation of A20 by IKKß thus represents part of a novel feedback loop that regulates the duration of NF-B signaling following activation of innate immune signaling pathways.

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* Corresponding author. Mailing address: Department of Pathology, Case Western Reserve University, Room 6136 Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106. Phone: (216) 368-8564. Fax: (216) 368-1357. E-mail: dwa4{at}case.edu

Published ahead of print on 20 August 2007.

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Molecular and Cellular Biology, November 2007, p. 7451-7461, Vol. 27, No. 21
0270-7306/07/$08.00+0     doi:10.1128/MCB.01101-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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