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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFα-induced JNK activation
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E3 ubiquitin ligase Mule ubiquitinates Miz1 and is required for TNFα-induced JNK activation

机译：E3泛素连接酶Mule泛素化Miz1，是TNFα诱导JNK激活所必需的

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摘要

The zinc finger transcription factor Miz1 is a negative regulator of TNFa-induced JNK activation and cell death through inhibition of TRAF2 K63-polyubiquitination in a transcription-independent manner. Upon TNFα stimulation, Miz1 undergoes K48-linked polyubiquiti-nation and proteasomal degradation, thereby relieving its inhibition. However, the underling regulatory mechanism is not known. Here, we report that HECT-domain-containing Mule is the E3 ligase that catalyzes TNFα-induced Miz1 polyubiquitination. Mule is a Miz1-associated protein and catalyzes its K48-linked polyubiquitination. TNFa-induced polyubiquitination and degradation of Miz1 were inhibited by silencing of Mule and were promoted by ectopic expression of Mule. The interaction between Mule and Miz1 was promoted by TNFa independently of the pox virus and zinc finger domain of Miz1. Silencing of Mule stabilized Miz1, thereby suppressing TNFa-induced JNK activation and cell death. Thus, our study reveals a molecular mechanism by which Mule regulates TNFα-induced JNK activation and apoptosis by catalyzing the polyubiquitination of Miz1.
机译：锌指转录因子Miz1是TNFa诱导的JNK激活和细胞死亡的负调控因子，它通过以独立于转录的方式抑制TRAF2 K63-多聚泛素化来发挥作用。在TNFα刺激下，Miz1经历K48连接的多泛素化和蛋白酶体降解，从而减轻了其抑制作用。但是，底层调控机制尚不清楚。在这里，我们报告说，包含HECT域的is子是E3连接酶，可催化TNFα诱导的Miz1多聚泛素化。 ule子是一种与Miz1相关的蛋白质，并催化其K48连接的多泛素化作用。 TNFa诱导的Mubi泛素化和Miz1的降解被沉默的ule子抑制和异位表达的promote子促进。 Mule和Miz1之间的相互作用是由TNFa促进的，独立于Miz1的痘病毒和锌指结构域。沉默ule子可稳定Miz1，从而抑制TNFa诱导的JNK活化和细胞死亡。因此，我们的研究揭示了一种分子机制，M子通过催化Miz1的多聚泛素化来调节TNFα诱导的JNK激活和凋亡。

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  • 作者

    Yi Yang; rnHanhChi Do; rnXuejun Tian; rnChaozheng Zhang; rnXinyuan Liu; rnLaura A. Dada; rnJacob I. Sznajder; Jing Liu;

  • 作者单位

    Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 Xinyuan Institute of Medicine and Biotechnology, College of Life Science, Zhejiang Sci-Tech University, Hangzhou 310018, China;

    rnDivision of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;

    rnDivision of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611 Xinyuan Institute of Medicine and Biotechnology, College of Life Science, Zhejiang Sci-Tech University, Hangzhou 310018, China;

    rnDivision of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;

    rnXinyuan Institute of Medicine and Biotechnology, College of Life Science, Zhejiang Sci-Tech University, Hangzhou 310018, China;

    rnDivision of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;

    rnDivision of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;

    rnDivision of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;

  • 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);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    Mule/ARF-BP1; TNFα signaling; Miz1 ubiquitination;

    机译：ule子/ ARF-BP1;TNFα信号;Miz1泛素化;

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