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J. Biol. Chem., Vol. 283, Issue 21, 14654-14664, May 23, 2008

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Pellino 3b Negatively Regulates Interleukin-1-induced TAK1-dependent NFB Activation^*

Hui Xiao, Wen Qian, Kirk Staschke, Youcun Qian, Grace Cui, Li Deng^¶, Mariam Ehsani, Xiliang Wang, Yue-Wei Qian, Zhijian J. Chen^¶, Raymond Gilmour, Zhengfan Jiang^||1, and Xiaoxia Li²

From the Department of Immunology, Cleveland Clinic Foundation, Cleveland, Ohio 44195, Lilly Research Laboratories, Indianapolis, Indiana 46285, ^¶Howard Hughes Medical Institute, Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, and ^||Peking University, Beijing 00871, China

IL-1 receptor-associated kinase (IRAK) is phosphorylated, ubiquitinated, and degraded upon interleukin-1 (IL-1) stimulation. In this study, we showed that IRAK can be ubiquitinated through both Lys-48- and Lys-63-linked polyubiquitin chains upon IL-1 induction. Pellino 3b is the RING-like motif ubiquitin protein ligase that promotes the Lys-63-linked polyubiquitination on IRAK. Pellino 3b-mediated Lys-63-linked IRAK polyubiquitination competed with Lys-48-linked IRAK polyubiquitination for the same ubiquitination site, Lys-134 of IRAK, thereby blocking IL-1-induced IRAK degradation. Importantly, the negative impact of Pellino 3b on IL-1-induced IRAK degradation correlated with the inhibitory effect of Pellino 3b on the IL-1-induced TAK1-dependent pathway, suggesting that a positive role of IRAK degradation in IL-1 induced TAK1 activation. Taken together, our results suggest that Pellino 3b acts as a negative regulator for IL-1 signaling by regulating IRAK degradation through its ubiquitin protein ligase activity.

Received for publication, August 20, 2007 , and in revised form, March 6, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant RO1 GM 060020-06 (to X. L.). 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 Fig. 1.

¹ To whom correspondence may be addressed: Dept. of Cell Biology and Genetics, School of Life Sciences, Peking University, Beijing 100871, China. Tel.: 8610-62757923; E-mail: jiangzf{at}pku.edu.cn. ² To whom correspondence may be addressed: Dept. of Immunology, Cleveland Clinic Foundation, 9500 Euclid Ave. NE40, Cleveland, OH 44195. Tel.: 216-445-8706; E-mail: lix{at}ccf.org.

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