Miz1 is a signal- and pathway-specific modulator or regulator (SMOR) that suppresses TNF-α-induced JNK1 activation
Miz1 is a signal- and pathway-specific modulator or regulator (SMOR) that suppresses TNF-α-induced JNK1 activation
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DOI：
10.1073/pnas.0906328106
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发表时间：
2009-10-27
影响因子：
11.1
通讯作者：
Lin, Anning
中科院分区：
文献类型：
--
作者：
Liu, Jing;Zhao, Yingming;Lin, Anning
促炎细胞因子TNF-α通过激活包括JNK 1在内的多种下游效应子发挥其多效性功能。然而，根本的监管机制并不完全清楚。在这里，我们报告说，转录因子Myc相互作用的锌指蛋白1（Miz 1）选择性抑制TNF-α诱导的JNK 1的激活和细胞死亡独立于其转录活性。蛋白质组学分析和酵母双杂交筛选表明Miz 1是一个JNK相关蛋白。TNF-α诱导的JNK 1活化在Miz 1缺陷型小鼠胚胎成纤维细胞（Miz 1（-/-）MEFs）中增强，但通过重新引入Miz 1或其转录缺陷型突变体消除了增强作用。Miz 1的调节是高度特异性的，因为它调节TNF-α诱导的TRAF 2 K63连接的多聚泛素化。IL-1 β或UV引起的JNK 1活化和TNF-α诱导的p38、ERK或I κ B激酶复合物的活化均不受Miz 1缺失的影响。TNF-α诱导的细胞死亡也在Miz 1（-/-）MEFs中加速。在TNF-α刺激下，Miz 1被蛋白酶体迅速降解，从而缓解其对JNK 1活化的抑制。因此，我们的研究结果表明，除了作为一个转录因子Miz 1作为一个信号和途径特异性调制器或调节器，特异性调节TNF-α诱导的JNK 1激活和细胞死亡。
The proinflammatory cytokine TNF-alpha exerts its pleiotropic functions through activation of multiple downstream effectors, including JNK1. Yet, the underlying regulatory mechanism is incompletely understood. Here, we report that the transcription factor Myc-interacting zinc-finger protein 1 (Miz1) selectively suppresses TNF-alpha-induced JNK1 activation and cell death independently of its transcription activity. Proteomics analysis and yeast two-hybrid screening reveal that Miz1 is a JNK-associated protein. The TNF-alpha induced activation of JNK1 is augmented in Miz1-deficient mouse embryonic fibroblasts (Miz1(-/-) MEFs), but the augmentation is abrogated by reintroduction of Miz1 or its transcription-deficient mutant. The regulation by Miz1 is highly specific, because it regulates TNF-alpha-induced TRAF2 K63-linked polyubiquitination. Neither JNK1 activation by IL-1 beta or UV nor TNF-alpha-induced activation of p38, ERK, or I kappa B kinase complex is affected by the loss of Miz1. The TNF-alpha-induced cell death also is accelerated in Miz1(-/-) MEFs. Upon TNF-alpha stimulation, Miz1 is degraded rapidly by the proteasome, relieving its suppression on JNK1 activation. Thus, our results show that in addition to being a transcription factor Miz1 acts as a signal-and pathway-specific modulator or regulator that specifically regulates TNF-alpha-induced JNK1 activation and cell death.