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Molecular and Cellular Biology, May 2005, p. 3886-3895, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.3886-3895.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Regulation of the Deubiquitinating Enzyme CYLD by IB Kinase Gamma-Dependent Phosphorylation

William Reiley, Minying Zhang, Xuefeng Wu, Erica Granger, and Shao-Cong Sun^*

Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, 500 University Dr., Hershey, Pennsylvania 17033

Received 31 October 2004/ Returned for modification 7 December 2004/ Accepted 15 February 2005

Tumor suppressor CYLD is a deubiquitinating enzyme (DUB) that inhibits the ubiquitination of key signaling molecules, including tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2). However, how the function of CYLD is regulated remains unknown. Here we provide evidence that inducible phosphorylation of CYLD is an important mechanism of its regulation. Under normal conditions, CYLD dominantly suppresses the ubiquitination of TRAF2. In response to cellular stimuli, CYLD undergoes rapid and transient phosphorylation, which is required for signal-induced TRAF2 ubiquitination and activation of downstream signaling events. Interestingly, the CYLD phosphorylation requires IB kinase gamma (IKK) and can be induced by IKK catalytic subunits. These findings suggest that CYLD serves as a novel target of IKK and that the site-specific phosphorylation of CYLD regulates its signaling function.

Supplemental material for this article may be found at http://mcb.asm.org/.

These authors contributed equally to this work.

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