The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway
The Yersinia enterocolitica effector YopP inhibits host cell signalling by inactivating the protein kinase TAK1 in the IL-1 signalling pathway
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DOI：
10.1038/sj.embor.7400754
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发表时间：
2006-08-01
期刊：
影响因子：
7.7
通讯作者：
Kracht, Michael
中科院分区：
文献类型：
--
作者：
Thiefes, Axel;Wolf, Alexander;Kracht, Michael
YopP 同时抑制丝裂原激活蛋白激酶 (MAPK) 和核因子-κ B 通路的机制尚不清楚。 YopP 的异位表达会抑制由过表达的 TGF-β 激活激酶 1 (TAK1) 及其亚基 TAK1 结合蛋白 (TAB) 1 组成的复合物的活性和泛素化，但不会抑制 MEK 激酶 1。YopP（而非催化失活突变体 YopP(C172A)）也会抑制内源性 TAK1 的基础激活和白细胞介素 1 诱导激活， TAB1 和 TAB2。 YopP 不影响 TAK1、TAB1 和 TAB2 的相互作用，但抑制 TAK1 在 Thr 187 处的自磷酸化和 TAB1 在 Ser 438 处的磷酸化。谷胱甘肽 S 转移酶标记的 YopP (GST-YopP) 在体外与 MAPK 激酶 (MAPKK) 4 和 TAB1 结合，但不与 TAK1 或 TAB2 结合。此外，YopP 与先前描述的负调节反馈环路协同作用，通过 MAPKK6 p38 介导的 TAB1 磷酸化抑制 TAK1。总而言之，这些数据强烈表明 YopP 与 TAB1 结合，并通过影响 TAK1 的组成型 TAK1 和 TAB1 泛素化（这是 TAK1 自身激活所需的）来直接抑制 TAK1 活性。
The mechanism by which YopP simultaneously inhibits mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B pathways has been elusive. Ectopic expression of YopP inhibits the activity and ubiquitination of a complex consisting of overexpressed TGF-beta-activated kinase 1 (TAK1) and its subunit TAK1-binding protein (TAB) 1, but not of MEK kinase 1. YopP, but not the catalytically inactive mutant YopP(C172A), also suppresses basal and interleukin-1-inducible activation of endogenous TAK1, TAB1 and TAB2. YopP does not affect the interaction of TAK1, TAB1 and TAB2 but inhibits autophosphorylation of TAK1 at Thr 187 and phosphorylation of TAB1 at Ser 438. Glutathione S-transferase-tagged YopP (GST-YopP) binds to MAPK kinase ( MAPKK) 4 and TAB1 but not to TAK1 or TAB2 in vitro. Furthermore, YopP in synergy with a previously described negative regulatory feedback loop inhibits TAK1 by MAPKK6 p38-mediated TAB1 phosphorylation. Taken together, these data strongly suggest that YopP binds to TAB1 and directly inhibits TAK1 activity by affecting constitutive TAK1 and TAB1 ubiquitination that is required for autoactivation of TAK1.