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J. Biol. Chem., Vol. 278, Issue 49, 48903-48906, December 5, 2003

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Signal-induced Ubiquitination of IB Kinase-^*

Robert S. Carter, Kevin N. Pennington, Bradley J. Ungurait, Pia Arrate, and Dean W. Ballard

From the Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0295

Initiation of the genetic programs for inflammation and immunity involves nuclear mobilization of transcription factor NF-B. This signal-dependent process is controlled in part by the -catalytic subunit of IB kinase (IKK), which marks IB and other cytoplasmic inhibitors of NF-B for proteolytic destruction. The catalytic activity of IKK is stimulated by pathologic and physiologic inducers of NF-B, such as the Tax oncoprotein and proinflammatory cytokines. We now report evidence that these NF-B inducers target IKK for conjugation to ubiquitin (Ub) in mammalian cells. The apparent molecular size of modified IKK is compatible with monoubiquitination rather than attachment of a multimeric Ub chain. The modification is contingent upon signal-induced phosphorylation of the activation T loop in IKK at Ser-177/Ser-181. The formation of IKK-Ub conjugates is disrupted in cells expressing YopJ, a Ub-like protein protease that interferes with the NF-B signaling pathway. These findings indicate an important mechanistic link between phosphorylation, ubiquitination, and the biologic action of IKK.

Received for publication, September 26, 2003

^* This work was supported by Grants CA082556, AI052379, and HL68744 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Training Grant T32 CA09385.

To whom correspondence should be addressed: Vanderbilt University School of Medicine, A4301 Medical Center N., 1161 21^st Avenue S., Nashville, TN 37232-2363. Tel.: 615-343-1918; Fax: 615-343-5743; E-mail: dean.ballard{at}vanderbilt.edu.

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