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J. Biol. Chem., Vol. 279, Issue 42, 43675-43683, October 15, 2004

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Interaction of TRAF6 with MAST205 Regulates NF-B Activation and MAST205 Stability^*

Huabao Xiong, Hongxing Li, Yibang Chen¶, Jie Zhao, and Jay C. Unkeless||

From the Immunobiology Center and the ^¶Department of Pharmacology and Biochemistry, Mount Sinai School of Medicine, New York, New York 10029

The binding of immune complexes to macrophage Fc receptor results in a subsequent inhibition of lipopolysaccharide-stimulated interleukin-12 synthesis without affecting the induction of tumor necrosis factor-. RNA interference targeting MAST205, a 205-kDa serine/threonine kinase, and transfection of dominant negative MAST205 mutants also mimic this type II macrophage phenotype. Our previous epistasis experiments suggested that the position of MAST205 in the TLR4 signal pathway was proximal to the IB kinase complex. We now report that MAST205 forms a complex with TRAF6, resulting in the inhibition of TRAF6 NF-B activation. We have identified a peptide (residues 218–233) from the N terminus of MAST205 that, when coupled to a protein transduction domain, inhibits the lipopolysaccharide-stimulated activation of NF-B, modulates the size of the MAST205·TRAF6 complex, and inhibits ubiquitination of TRAF6. A dominant negative N-terminal MAST205 deletion mutant also inhibits TRAF6 ubiquitination. The domain required for degradation of MAST205 after Fc receptor activation resides within the N-terminal 261 residues, and degradation is triggered by protein kinase C isoform phosphorylation of Ser/Thr residues. These results suggest that MAST205 functions as a scaffolding protein controlling TRAF6 activity and, therefore, plays an important role in regulating inflammatory responses.

Received for publication, April 19, 2004 , and in revised form, July 14, 2004.

^* This work was supported by National Institutes of Health Grant AI-24322 and AI-52325 (to J. C. U.) and a Crohn's and Colitis Foundation of America First Award (to H. X.). 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.

Both investigators participated equally in this work.

^|| To whom correspondence should be addressed: Immunobiology Center, Mount Sinai School of Medicine, 1425 Madison Ave., New York City, NY 10029. Tel.: 212-659-9402; Fax: 212-849-2525; E-mail: jay.unkeless{at}mssm.edu .

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