Activation or suppression of NFκB by HPK1 determines sensitivity to activation-induced cell death
Activation or suppression of NFκB by HPK1 determines sensitivity to activation-induced cell death
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DOI：
10.1038/sj.emboj.7600894
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发表时间：
2005-12-21
期刊：
影响因子：
11.4
通讯作者：
Arnold, R
中科院分区：
文献类型：
--
作者：
Brenner, D;Golks, A;Arnold, R
活化 T 细胞中 T 细胞受体 (TCR) 的再刺激会诱导 CD95 (Fas/Apo-1) 介导的活化诱导细胞死亡 (AICD)。导致 AICD 的 TCR 近端机制尚不清楚。在这里，我们将造血祖激酶 1 (HPK1) 描述为一种差异调节的 TCR 近端信号蛋白，参与原代 T 细胞的 AICD。我们证明 HPK1 是内源性 I kappa B 激酶 (IKK) 复合物的功能成分，对于 TCR 介导的 NF kappa B 激活至关重要。虽然全长 HPK1 增强 IKK β 磷酸化，但 siRNA 介导的 HPK1 敲低会减弱 TCR 介导的 NF kappa B 激活并增加细胞死亡。我们还证明了 HPK1 蛋白水解加工成 HPK1-C，特别是在 AICD 敏感的原代 T 细胞中。裂解产物 HPK1-C 通过与 IKK α 和 IKK β 结合来隔离无活性的 IKK 复合物并在 TCR 再刺激时抑制 NF kappa B。 HPK1-C 转基因小鼠的 T 细胞对 TCR 介导的 AICD 敏感。因此，通过 siRNA 介导的敲低来阻止原代 T 细胞中 HPK1-C 的生成会导致 AICD 降低。因此，这些结果显示了通过抑制 NF kappa B 使 T 淋巴细胞对 AICD 敏感的新机制，并提出 HPK1 是 T 淋巴细胞中的生/死开关。
Restimulation of the T-cell receptor (TCR) in activated T cells induces CD95 (Fas/Apo-1)-mediated activation-induced cell death (AICD). The TCR-proximal mechanisms leading to AICD are elusive. Here we characterize hematopoietic progenitor kinase 1 (HPK1) as a differentially regulated TCR-proximal signaling protein involved in AICD of primary T cells. We show that HPK1 is a functional component of the endogenous I kappa B kinase (IKK) complex and is crucial for TCR-mediated NF kappa B activation. While full-length HPK1 enhances IKK beta phosphorylation, siRNA-mediated knockdown of HPK1 blunts TCR-mediated NF kappa B activation and increases cell death. We also demonstrate proteolytic processing of HPK1 into HPK1-C, specifically in AICD-sensitive primary T cells. The cleavage product HPK1-C sequesters the inactive IKK complex and suppresses NF kappa B upon TCR restimulation by binding to IKK alpha and IKK beta. T cells of HPK1-C transgenic mice are sensitized towards TCR-mediated AICD. Consequently, preventing HPK1-C generation in primary T cells by siRNA-mediated knockdown results in decreased AICD. Thus, these results show a novel mechanism of sensitization of T lymphocytes towards AICD by suppression of NF kappa B, and propose that HPK1 is a life/death switch in T lymphocytes.