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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Pairwise network mechanisms in the host signaling response to coxsackievirus B3 infection
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Pairwise network mechanisms in the host signaling response to coxsackievirus B3 infection

机译：宿主对柯萨奇病毒B3感染的信号响应中的成对网络机制

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摘要

Signal transduction networks can be perturbed biochemically, genetically, and pharmacologically to unravel their functions. But at the systems level, it is not clear how such perturbations are best implemented to extract molecular mechanisms that underlie network function. Here, we combined pairwise perturbations with murtipa-rameter phosphorylation measurements to reveal causal mechanisms within the signaling network response of cardiomyocytes to coxsackievirus B3 (CVB3) infection. Using all possible pairs of six kinase inhibitors, we assembled a dynamic nine-protein phosphorylation signature of perturbed CVB3 infectivity. Cluster analysis of the resulting dataset showed repeatedly that paired inhibitor data were required for accurate data-driven predictions of kinase substrate links in the host network. With pairwise data, we also derived a high-confidence network based on partial correlations, which identified phospho-licBa as a central "hub" in the measured phosphorylation signature. The reconstructed network helped to connect phospho-IκBα with an autocrine feedback circuit in host cells involving the proinflammatory cytokines, TNF and IL-1. Autocrine blockade substantially inhibited CVB3 progeny release and improved host cell viability, implicating TNF and IL-1 as cell autonomous components of CVB3-induced myocardial damage. We conclude that pairwise perturbations, when combined with network-level intracellular measurements, enrich for mechanisms that would be overlooked by single perturbants.
机译：信号转导网络可能会在生化，遗传和药理上受到干扰，以发挥其功能。但是在系统层面，尚不清楚如何最好地实现这种扰动来提取构成网络功能基础的分子机制。在这里，我们结合成对的扰动与Murtipa-rameter磷酸化测量结果来揭示心肌细胞对柯萨奇B3（CVB3）感染的信号网络响应内的因果机制。使用所有可能的六种激酶抑制剂对，我们组装了扰动的CVB3感染力的动态九蛋白磷酸化标记。所得数据集的聚类分析反复表明，成对的抑制剂数据是宿主网络中激酶底物链接的准确数据驱动预测所必需的。利用成对数据，我们还基于部分相关性推导了高可信度网络，该网络将phospho-licBa确定为测得的磷酸化标记中的中心“集线器”。重建的网络有助于在参与促炎细胞因子，TNF和IL-1的宿主细胞中将磷酸化IκBα与自分泌反馈回路连接起来。自分泌阻滞剂实质上抑制了CVB3的后代释放并改善了宿主细胞的生存能力，提示TNF和IL-1是CVB3诱导的心肌损伤的细胞自主成分。我们得出结论，当与网络级细胞内测量结合使用时，成对扰动会丰富单个扰动器会忽略的机制。

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    Farshid S. Garmaroudi; David Marchant; Xiaoning Si; Abbas Khalili; Ali Bashashati; Brian W. Wong; Aline Tabet; Raymond T. Ng; Kevin Murphy; Honglin Luo; Kevin A. Janes; Bruce M. McManus;

  • 作者单位

    The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Providence Heart and Lung Institute at St. Paul's Hospital,University of British Columbia, Vancouver, BC, Canada V62 1Y6 Departments of Pathology and Laboratory Medicine,University of British Columbia, Vancouver, BC, Canada V62 1Y6;

    rnThe James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Providence Heart and Lung Institute at St. Paul's Hospital,University of British Columbia, Vancouver, BC, Canada V62 1Y6 Departments of Pathology and Laboratory Medicine,University of British Columbia, Vancouver, BC, Canada V62 1Y6;

    rnThe James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Providence Heart and Lung Institute at St. Paul's Hospital,University of British Columbia, Vancouver, BC, Canada V62 1Y6 Departments of Pathology and Laboratory Medicine,University of British Columbia, Vancouver, BC, Canada V62 1Y6;

    rnDepartment of Mathematics and Statistics, McGill University, Montreal, QC, Canada H3A 2K6;

    rnDepartments of Terry Fox Laboratory-British Columbia Cancer Agency, University of British Columbia, Vancouver, BC, Canada V62 1Y6;

    rnThe James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Providence Heart and Lung Institute at St. Paul's Hospital,University of British Columbia, Vancouver, BC, Canada V62 1Y6 Departments of Pathology and Laboratory Medicine,University of British Columbia, Vancouver, BC, Canada V62 1Y6;

    rnDepartments of Statistics, University of British Columbia, Vancouver, BC, Canada V62 1Y6;

    rnThe James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Providence Heart and Lung Institute at St. Paul's Hospital,University of British Columbia, Vancouver, BC, Canada V62 1Y6 Departments of Computer Science, University of British Columbia, Vancouver, BC, Canada V62 1Y6;

    rnDepartments of Statistics, University of British Columbia, Vancouver, BC, Canada V62 1Y6 Departments of Computer Science, University of British Columbia, Vancouver, BC, Canada V62 1Y6;

    rnThe James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Providence Heart and Lung Institute at St. Paul's Hospital,University of British Columbia, Vancouver, BC, Canada V62 1Y6 Departments of Pathology and Laboratory Medicine,University of British Columbia, Vancouver, BC, Canada V62 1Y6;

    rnDepartment of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908;

    rnThe James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Providence Heart and Lung Institute at St. Paul's Hospital,University of British Columbia, Vancouver, BC, Canada V62 1Y6 Departments of Pathology and Laboratory Medicine,University of British Columbia, Vancouver, BC, Canada V62 1Y6;

  • 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

    pairwise perturbation; signaling network; systems biology; viral myocarditis; picornaviridae;

    机译：成对摄动信令网络;系统生物学;病毒性心肌炎皮科病毒科;

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