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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Epithelial transforming growth factor β-activated kinase 1 (TAK1) is activated through two independent mechanisms and regulates reactive oxygen species
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Epithelial transforming growth factor β-activated kinase 1 (TAK1) is activated through two independent mechanisms and regulates reactive oxygen species

机译：上皮转化生长因子β活化激酶1（TAK1）通过两个独立的机制被激活并调节活性氧

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摘要

Dysregulation in cellular redox systems results in accumulation of reactive oxygen species (ROS), which are causally associated with a number of disease conditions. Transforming growth factor β-activated kinase 1 (TAK1) is a signaling intermediate of innate immune signaling pathways and is critically involved in the redox regulation in vivo. Ablation of TAK1 causes accumulation of ROS, resulting in epithelial cell death and inflammation. Here we determine the mechanism by which TAK1 kinase is activated in epithelial tissues. TAB1 and TAB2 are structurally unrelated TAK1 binding protein partners. TAB2 is known to mediate polyubiquitin chain-dependent TAK1 activation in innate immune signaling pathways, whereas the role of TAB1 is not defined. We found that epithelial-specific TAB1 and TAB2 double- but not TAB1 or TAB2 single-knockout mice phenocopied epithelial-specific TAK1 knockout mice. We demonstrate that phosphorylation-dependent basal activity of TAK1 is dependent on TAB1. Ablation of both TAB1 and TAB2 diminished the activity of TAK1 in vivo and causes accumulation of ROS in the epithelial tissues. These results demonstrate that epithelial TAK1 activity is regulated through two unique, TAB1-dependent basal and TAB2-mediated stimuli-dependent mechanisms.
机译：细胞氧化还原系统中的失调导致活性氧（ROS）的积累，这与许多疾病状况有因果关系。转化生长因子β活化激酶1（TAK1）是先天性免疫信号传导途径的信号传导中间体，并且在体内主要参与氧化还原调节。 TAK1的切除导致ROS的积累，导致上皮细胞死亡和炎症。在这里，我们确定TAK1激酶在上皮组织中被激活的机制。 TAB1和TAB2是结构上不相关的TAK1结合蛋白伴侣。已知TAB2在先天性免疫信号传导途径中介导多聚泛素链依赖性TAK1激活，而TAB1的作用尚未定义。我们发现上皮特异性TAB1和TAB2双重但不是TAB1或TAB2单敲除小鼠表型上皮特异性TAK1敲除小鼠。我们证明了TAK1的磷酸化依赖性基础活性取决于TAB1。 TAB1和TAB2的消融会减少TAK1在体内的活性，并导致ROS在上皮组织中积聚。这些结果表明上皮TAK1活性是通过两个独特的，TAB1依赖的基础和TAB2介导的刺激依赖的机制来调节的。

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    Emily Omori; Maiko lnagaki; Yuji Mishina; Kunihiro Matsumoto; Jun Ninomiya-Tsuji;

  • 作者单位

    Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633;

    Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633;

    Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Ml 48109-1078;

    Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, 464-8602 Japan;

    Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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