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J. Biol. Chem., Vol. 280, Issue 25, 23531-23539, June 24, 2005

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Ubiquitin-dependent Degradation of Interferon Regulatory Factor-8 Mediated by Cbl Down-regulates Interleukin-12 Expression^*

Huabao Xiong, Hongxing Li, Hee Jeong Kong¶, Yibang Chen||, Jie Zhao, Sidong Xiong**, Bo Huang, Hua Gu, Lloyd Mayer, Keiko Ozato¶, and Jay C. Unkeless¶¶

From the Immunobiology Center, Mount Sinai School of Medicine, New York, New York 10029, ^¶Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, ^**Department of Immunology, Shanghai Medical College, Fudan University, Shanghai 200025, China, Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, Department of Microbiology and Immunology, Columbia University School of Physicians and Surgeons, New York, New York 10032, and ^||Department of Pharmacology, Mount Sinai School of Medicine, New York, New York 10029

Interferon regulatory factor (IRF)-8/interferon consensus sequence-binding protein is regulated by both transcription and degradation. IRF-8 induced in peritoneal macrophages by interferon- and lipopolysaccharide was degraded rapidly, and degradation of IRF-8 was blocked by MG132, the proteasome inhibitor, but inhibitors of calpain and lysosomal enzymes had no effect. The ubiquitination of IRF-8 was shown by co-immunoprecipitation from RAW264.7 macrophages retrovirally transduced with IRF-8 and hemagglutinin-ubiquitin. The dominant negative ubiquitin mutants K48R and K29R inhibited IRF-8 degradation in 293T cells, confirming the relationship between ubiquitination of IRF-8 and its degradation. IRF-8 carboxyl-terminal truncation mutants were not ubiquitinated and were consequently stable, indicating that the carboxyl-terminal domain of IRF-8 controls ubiquitination. The ubiquitin-protein isopeptide ligase (E3) that ubiquitinated IRF-8 was likely to be Cbl, which formed a complex with IRF-8, demonstrable by both immunoprecipitation and gel filtration. Furthermore, IRF-8 stability was increased by dominant negative Cbl, and IRF-8 ubiquitination was significantly attenuated in Cbl–/– cells. Reflecting increased stability and expression, the IRF-8 carboxyl-terminal deletion mutant induced interleukin (IL)-12 p40 promoter activity much more strongly than IRF-8 did. Furthermore, IRF-8-induced IL-12 p40 synthesis in RAW264.7 cells was enhanced by dominant negative Cbl, and peritoneal macrophages from Cbl–/– mice showed increased IL-12 p40 protein production. Taken together, these results suggest that the proteasomal degradation of IRF-8 mediated by the ubiquitin E3 ligase Cbl down-regulates IL-12 expression.

Received for publication, December 20, 2004 , and in revised form, March 21, 2005.

^* 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 National Institutes of Health Grants AI-24322 and AI52325.

Supported by Crohn's and Colitis Foundation of America Grant 02-0040IB. To whom correspondence should be addressed: Immunobiology Center, Box 1630, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029-6574. Tel.: 212-659-9413; Fax: 212-849-2525; E-mail: xionghbl{at}yahoo.com.

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