Interaction of TRAF6 with MAST205 regulates NF-κB activation and MAST205 stability
Interaction of TRAF6 with MAST205 regulates NF-κB activation and MAST205 stability
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DOI：
10.1074/jbc.m404328200
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发表时间：
2004-10-15
影响因子：
4.8
通讯作者：
Unkeless, JC
中科院分区：
文献类型：
--
作者：
Xiong, HB;Li, HX;Unkeless, JC
免疫复合物与巨噬细胞Fc γ受体的结合导致脂多糖刺激的白细胞介素-12合成的随后抑制，而不影响肿瘤坏死因子-α的诱导。靶向MAST 205（一种205-kDa丝氨酸/苏氨酸激酶）的RNA干扰和显性阴性MAST 205突变体的转染也模拟了这种II型巨噬细胞表型。我们先前的上位性实验表明MAST 205在TLR 4信号通路中的位置接近IkappaB激酶复合物。我们现在报道MAST 205与TRAF 6形成复合物，导致TRAF 6 NF-κ B活化的抑制。我们已经从MAST 205的N末端鉴定了一种肽（残基218 - 233），当其与蛋白转导结构域偶联时，抑制脂多糖刺激的NF-κ B活化，调节MAST 205的大小。TRAF 6复合物，并抑制TRAF 6的泛素化。显性负性N-末端MAST 205缺失突变体也抑制TRAF 6泛素化。Fc γ受体活化后MAST 205降解所需的结构域位于N-末端261个残基内，并且降解由Ser/Thr残基的蛋白激酶C同种型磷酸化触发。这些结果表明，MAST 205的功能作为一个支架蛋白控制TRAF 6的活性，因此，在调节炎症反应中起着重要的作用。
The binding of immune complexes to macrophage Fcgamma receptor results in a subsequent inhibition of lipopolysaccharide-stimulated interleukin-12 synthesis without affecting the induction of tumor necrosis factor-alpha. 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 IkappaB kinase complex. We now report that MAST205 forms a complex with TRAF6, resulting in the inhibition of TRAF6 NF-kappaB 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-kappaB, 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 Fcgamma 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.