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J. Biol. Chem., Vol. 283, Issue 27, 18621-18626, July 4, 2008

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Regulation of IB Kinase-related Kinases and Antiviral Responses by Tumor Suppressor CYLD^*

Minying Zhang¹, Xuefeng Wu¹, Andrew J. Lee, Wei Jin, Mikyoung Chang, Ato Wright, Tadaatsu Imaizumi^¶, and Shao-Cong Sun²

From the Department of Immunology, the University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, the Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, and the ^¶Department of Vascular Biology, Hirosaki University School of Medicine, Hirosaki 036-8562, Japan

The IB kinase (IKK)-related kinases, IKK and TBK1, participate in the induction of type I interferons (IFNs) during viral infections. Deregulated activation of IKK and TBK1 also contributes to the abnormal cell survival and transformation. However, how these kinases are negatively regulated remains unclear. We show here that the tumor suppressor CYLD has an essential role in preventing aberrant activation of IKK/TBK1. CYLD deficiency causes constitutive activation of IKK/TBK1, which is associated with hyper-induction of IFNs in virus-infected cells. We further show that CYLD targets a cytoplasmic RNA sensor, RIG-I, and inhibits the ubiquitination of this IKK/TBK1 stimulator. Consistent with the requirement of ubiquitination in RIG-I function, CYLD potently inhibits RIG-I-mediated activation of the IFN-β promoter. These findings establish CYLD as a key negative regulator of IKK/TBK1 and suggest a role for CYLD in the control of RIG-I ubiquitination.

Received for publication, February 22, 2008 , and in revised form, May 8, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants AI064639, AI057555, and CA94922. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 713-563-3218; Fax: 713-563-3280; E-mail: ssun{at}mdanderson.org.

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