Tumor necrosis factor α-induced desumoylation and cytoplasmic translocation of homeodomain-interacting protein kinase 1 are critical for apoptosis signal-regulating kinase 1-JNK/p38 activation
Tumor necrosis factor α-induced desumoylation and cytoplasmic translocation of homeodomain-interacting protein kinase 1 are critical for apoptosis signal-regulating kinase 1-JNK/p38 activation
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DOI：
10.1074/jbc.m414262200
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发表时间：
2005-04-15
影响因子：
4.8
通讯作者：
Min, W
中科院分区：
文献类型：
--
作者：
Li, XH;Zhang, R;Min, W
凋亡信号调节激酶1 (ASK1)-JNK/ p38信号通路是细胞凋亡的关键组成部分，可被多种死亡刺激激活，包括肿瘤坏死因子(TNF) α和氧化应激（活性氧）。然而，ASK1激活的机制尚不完全清楚。我们最近发现ASK1相互作用蛋白（AIP1）是TNF α诱导的ASK1激活的新信号换能器，通过促进ASK1与其抑制剂14-3-3的解离。本研究采用酵母双杂交系统，以AIP1的n端结构域为诱饵，鉴定出同源结构域相互作用蛋白激酶1 （HIPK1）是AIP1的相关蛋白。有趣的是，我们发现TNF α诱导HIPK1去氧化，同时在15分钟内从细胞核转移到细胞质，然后在60分钟后返回细胞核。HIPK1易位动力学与应激诱导的ASK1-JNK/P38激活动力学相关。一种特异性的JNK抑制剂阻断了HIPK1的反向而非初始易位，这表明初始易位是ASK1-JNK/p38信号传导的上游事件，JNK激活作为一种反馈机制调节反向易位。一致地，HIPK1的表达增加，而激酶无活性形式（HIPK1- d315n）或HIPK1的小干扰RNA的表达降低了应激诱导的ASK1-JNK/P38激活，而不影响IKK-NF-kappa B信号传导。此外，HIPK1的summoylylation缺陷突变体（KR5）定位于细胞质，并在ASK1-JNK/P38激活中具有组成性活性。此外，HIPK1-KR5诱导ASK1与其抑制剂14-3-3和硫氧还蛋白分离，并与AIP1协同诱导ASK1活化。我们的研究表明，TNF α诱导的去氧化和HIPK1的细胞质易位是TNF α诱导的ASK1-JNK/p38激活的关键。
The apoptosis signal-regulating kinase 1 (ASK1)-JNK/ p38 signaling pathway is pivotal component in cell apoptosis and can be activated by a variety of death stimuli including tumor necrosis factor (TNF) alpha and oxidative stress ( reactive oxygen species). However, the mechanism for ASK1 activation is not fully understood. We have recently identified ASK1-interacting protein (AIP1) as novel signal transducer in TNF alpha-induced ASK1 activation by facilitating dissociation of ASK1 from its inhibitor 14-3-3. In the present study, we employed yeast two-hybrid system using the N-terminal domain of AIP1 as bait and identified homeodomain-interacting protein kinase 1 (HIPK1) as an AIP1-associated protein. Interestingly, we showed that TNF alpha induced HIPK1 desumoylation concomitant with a translocation from nucleus to cytoplasm at 15 min followed by a return to nucleus by 60 min. The kinetics of HIPK1 translocation correlates with those of stress-induced ASK1-JNK/P38 activation. A specific JNK inhibitor blocked the reverse but not the initial translocation of HIPK1, suggesting that the initial translocation is an upstream event of ASK1-JNK/p38 signaling and JNK activation regulates the reverse translocation as a feedback mechanism. Consistently, expression of HIPK1 increased, whereas expression of a kinase-inactive form (HIPK1-D315N) or small interference RNA of HIPK1 decreased stress-induced ASK1-JNK/P38 activation without effects on IKK-NF-kappa B signaling. Moreover, a sumoylation-defective mutant of HIPK1 (KR5) localizes to the cytoplasm and is constitutively active in ASK1-JNK/P38 activation. Furthermore, HIPK1-KR5 induces dissociation of ASK1 from its inhibitors 14-3-3 and thioredoxin and synergizes with AIP1 to induce ASK1 activation. Our study suggests that TNF alpha-induced desumoylation and cytoplasmic translocation of HIPK1 are critical in TNF alpha-induced ASK1-JNK/p38 activation.