Deltex regulates T-cell activation by targeted degradation of active MEKK1
Deltex regulates T-cell activation by targeted degradation of active MEKK1
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DOI：
10.1128/mcb.25.4.1367-1378.2005
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发表时间：
2005-02-01
影响因子：
5.3
通讯作者：
Lai, MZ
中科院分区：
文献类型：
--
作者：
Liu, WH;Lai, MZ
Deltex被称为Notch信号介质，但其生理作用机制却知之甚少。在这里，我们确定了 Deltex 在 T 细胞激活中的新调节作用。 Deltex 表达在静息 T 细胞中是组成型的，并且在 T 细胞受体 (TCR) 刺激激活后减少。当 Deltex1 被小干扰 RNA 下调时，T 细胞活化增强，支持了 Deltex 的生物学作用。 Deltex1 的过度表达抑制 T 细胞激活，但不抑制近端 TCR 激活事件。 Deltex 对丝裂原激活蛋白激酶的激活受损可能部分归因于 T 细胞中 MEKK1 蛋白的选择性下调。我们进一步发现 Deltex 促进了 MEKK1 C 端催化片段 [MEKK1(C)] 的降解。体内和体外泛素化分析显示，Deltex1 直接与 MEKK1(C) 相互作用并刺激 MEKK1(C) 泛素化。因此，MEKK1(C)（T 细胞中 MEKK1 的主要形式）是 Deltex E3 泛素连接酶的靶标。我们的结果揭示了 Deltex 如何通过关键信号分子 MEKK1 的降解来选择性抑制 T 细胞激活的新机制。
Deltex is known as a Notch signal mediator, but its physiological action mechanism is poorly understood. Here we identified a new regulatory role of Deltex in T-cell activation. Deltex expression was constitutive in resting T cells and was reduced upon T-cell receptor (TCR)-stimulated activation. The biological role of Deltex is supported by the enhanced T-cell activation when Deltex1 was down-regulated by small interfering RNA. Overexpression of Deltex1 suppressed T-cell activation but not the proximal TCR activation events. The impaired activation of mitogen-activated protein kinase by Deltex could be partly attributed to a selective down-regulation of MEKK1 protein in T cells. We further found that Deltex promoted degradation of the C-terminal catalytic fragment of MEKK1 [MEKK1(C)]. Deltex1 interacted directly with MEKK1(C) and stimulated the ubiquitination of MEKK1(C) as shown by in vivo and in vitro ubiquitination analysis. Therefore, MEKK1(C), the dominant form of MEKK1 in T cells, is a target of Deltex E3 ubiquitin ligase. Our results reveal a novel mechanism as to how Deltex selectively suppresses T-cell activation through degradation of a key signaling molecule, MEKK1.