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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >An IFN-γ-stimulated ATF6-C/EBP-SS-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy
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An IFN-γ-stimulated ATF6-C/EBP-SS-signaling pathway critical for the expression of Death Associated Protein Kinase 1 and induction of autophagy

机译：IFN-γ刺激的ATF6-C / EBP-SS信号通路对于死亡相关蛋白激酶1的表达和自噬的诱导至关重要

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摘要

The IFN family of cytokines operates a frontline defense against pathogens and neoplastic cells in vivo by controlling the expression of several genes. The death-associated protein kinase 1 (DAPK1), an IFN-γ-induced enzyme, controls cell cycle, apoptosis, autophagy, and tumor metastasis, and its expression is frequently down-regulated in a number of human tumors. Although the biochemical action of DAPK1 is well understood, mechanisms that regulate its expression are unclear. Previously, we have shown that transcription factor C/EBP-β is required for the basal and IFN-γ-induced expression of DAPK1. Here, we show that ATF6, an ER stress-induced transcription factor, interacts with C/EBP-β in an IFN-stimulated manner and is obligatory for Dapki expression. IFN-stimulated proteolytic processing of ATF6 and ERK1/2-mediated phosphorylation of C/EBP-β are necessary for these interactions. More importantly, IFN-γ failed to activate autophagic response in cells lacking either ATF6 or C/EBP-β. Consistent with these observations, the Atf6~(-/-) mice were highly, susceptible to lethal bacterial infections compared with the wild-type mice. These studies not only unravel an IFN signaling pathway that controls cell growth and antibacterial defense, but also expand the role of ATF6 beyond ER stress.
机译：通过控制几种基因的表达，细胞因子的IFN家族在体内对病原体和赘生性细胞进行一线防御。死亡相关蛋白激酶1（DAPK1）是一种IFN-γ诱导的酶，控制细胞周期，细胞凋亡，自噬和肿瘤转移，其表达在许多人类肿瘤中经常被下调。尽管DAPK1的生化作用已广为人知，但调节其表达的机制尚不清楚。先前，我们已经证明转录因子C /EBP-β是基础和IFN-γ诱导的DAPK1表达所必需的。在这里，我们显示ATF6，一种内质网应激诱导的转录因子，以IFN刺激的方式与C /EBP-β相互作用，并且对于Dapki表达是必需的。这些相互作用需要IFN刺激的ATF6蛋白水解过程和ERK1 / 2介导的C /EBP-β磷酸化。更重要的是，在缺乏ATF6或C /EBP-β的细胞中，IFN-γ无法激活自噬反应。与这些观察结果一致，与野生型小鼠相比，Atf6〜（-/-）小鼠高度易感染致死性细菌感染。这些研究不仅揭示了控制细胞生长和抗菌防御的IFN信号通路，而且将ATF6的作用扩展到了内质网应激之外。

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    Padmaja Gade; Girish Ramachandran; Uday B. Maachani; Mark A. Rizzo; Tetsuya Okada; Ron Prywes; Alan S. Cross; Kazutoshi Mori; Dhananjaya V. Kalvakolanu;

  • 作者单位

    Departments of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;

    Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201;

    Departments of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201;

    Departments of Physiology, and University of Maryland School of Medicine, Baltimore, MD 21201;

    Department of Biophysics, Graduate School of Science, Kyoto University, Kitashirakawa-oiwake, Sakyo-ku, Kyoto 606-8502, Japan;

    Department of Biological Sciences, Columbia University, New York, NY 10027;

    Departments of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201 Departments of Center for Vaccine Development, and University of Maryland School of Medicine, Baltimore, MD 21201;

    Department of Biophysics, Graduate School of Science, Kyoto University, Kitashirakawa-oiwake, Sakyo-ku, Kyoto 606-8502, Japan;

    Departments of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201 Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201;

  • 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
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  • 关键词

    signal transduction; tumor suppression; gene expression; innate immunity;

    机译：信号转导;肿瘤抑制;基因表达;先天免疫;

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