The interleukin-1 receptor associated kinase 1 contributes to the regulation of NFAT.
The interleukin-1 receptor associated kinase 1 contributes to the regulation of NFAT.
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IL-1 受体相关激酶 1 有助于 NFAT 的调节。
DOI：
10.1016/j.molimm.2008.06.023
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发表时间：
2008
影响因子：
3.6
通讯作者：
Li,Liwu
中科院分区：
文献类型：
--
作者：
Wang,Dongmei;Fasciano,Stephan;Li,Liwu
IRAK-1是调节先天免疫信号转导过程的重要调节因子。然而，IRAK-1的生理底物仍然不清楚。在这份报告中，我们已经证明了IRAK-1是一种负责活化T细胞核因子(NFAT)的结构性磷酸化和失活的激酶。IRAK-1的表达抑制了NFAT报告基因的活性。相应地，在IRAK-1−/−细胞中，核NFATc1和NFATc4的表达水平也呈结构性升高。此外，在IRAK-1−/−细胞中，S168PS170P位NFATC4的磷酸化水平显著降低。从机制上，我们观察到IRAK-1通过IRAK-1的C端和NFATc4的N端NHR区域与NFATc4相互作用。IRAK-1突变体可以阻断其激酶活性或与NFATc4的相互作用，但未能抑制NFAT报告基因的活性。NFAT调控的COX2在IRAK-1−/−细胞中的表达水平升高。从功能上讲，载脂蛋白E−/−/IRAK-1−/−小鼠对高脂饮食诱导的高血压和动脉粥样硬化具有保护作用。综上所述，我们的发现揭示了NFAT分子是IRAK-1的新的生理靶点。
IRAK-1 is a critical modulator regulating innate immunity signaling processes. However, the physiological substrates for IRAK-1 remain poorly defined. In this report, we have demonstrated that IRAK-1 is a kinase responsible for the constitutive phosphorylation and inactivation of the Nuclear Factor of Activated T-cell (NFAT). Expression of IRAK-1 suppressed NFAT reporter activity. Correspondingly, the levels of both nuclear NFATc1 and NFATc4 were constitutively elevated in IRAK-1−/−cells. Furthermore, the phosphorylation of NFATc4 at the S168PS170P site was significantly diminished in IRAK-1−/−cells. Mechanistically, we observed that IRAK-1 interacted with NFATc4 via the C-terminus of IRAK-1 and the N-terminal NHR region of NFATc4. IRAK-1 mutants that ablated either its kinase activity or its interaction with NFATc4 failed to suppress NFAT reporter activity. The expression level of COX2, which is under the control of NFAT, was elevated in IRAK-1−/−cells. Functionally, ApoE−/−/IRAK-1−/−mice were protected from high-fat-diet-induced hypertension and atherosclerosis. Taken together, our findings reveal NFAT molecules as novel physiological targets for IRAK-1.