Toll-like receptor 2-mediated NF-κB activation requires a RacI-dependent pathway
Toll-like receptor 2-mediated NF-κB activation requires a RacI-dependent pathway
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DOI：
10.1038/82797
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发表时间：
2000-12-01
影响因子：
30.5
通讯作者：
Knaus, UG
中科院分区：
文献类型：
--
作者：
Arbibe, L;Mira, JP;Knaus, UG
哺乳动物Toll样受体（TLRs）在先天免疫细胞上表达，并对革兰氏阳性或革兰氏阴性细菌的膜成分产生应答。当被激活时，它们将信号传递给调控炎症反应的转录因子。然而，TLR活化后的细胞内信号转导事件在很大程度上是未知的。在这里，我们表明，TLR 2刺激金黄色葡萄球菌诱导的Rho GTPases Rad和Cdc 42在人单核细胞系THP-I和293细胞表达TLR 2的快速和短暂的激活。显性负性RacIN 17，而不是显性负性Cdc 42 N17，阻断核因子-κ B（NF-κ B）的反式激活。金黄色葡萄球菌刺激导致活性Rad和磷脂酰肌醇-3激酶（PI 3 K）募集至TLR 2胞质结构域。TLR 2的酪氨酸磷酸化是组装多蛋白复合物所必需的，该复合物是后续NF-κ B转录活性所必需的。由Rad、PI 3 K和Akt组成的信号级联靶向核p65反式激活，而不依赖于I κ B α降解。因此，Rad控制第二个I κ B-独立的NF-κ B激活途径，并且在先天免疫细胞通过TLR 2的信号传导中是必需的。
Mammalian Toll-like receptors (TLRs) are expressed on innate immune cells and respond to the membrane components of Gram-positive or Gram-negative bacteria. When activated, they convey signals to transcription factors that orchestrate the inflammatory response. However, the intracellular signaling events following TLR activation are largely unknown. Here we show that TLR2 stimulation by Staphylococcus aureus induces a fast and transient activation of the Rho GTPases Rad and Cdc42 in the human monocytic cell line THP-I and in 293 cells expressing TLR2. Dominant-negative RacIN17,but not dominant-negative Cdc42N17, block nuclear factor-kappaB (NF-kappaB) transactivation. S, aureus stimulation causes the recruitment of active Rad and phosphatidylinositol-3 kinase (PI3K) to the TLR2 cytosolic domain. Tyrosine phosphorylation of TLR2 is required for assembly of a multiprotein complex that is necessary for subsequent NF-kappaB transcriptional activity. A signaling cascade composed of Rad, PI3K and Akt targets nuclear p65 transactivation independently of I kappaB alpha degradation, Thus Rad controls a second, I kappaB-independent, pathway to NF-kappaB activation and is essential in innate immune cell signaling via TLR2.