Pairwise network mechanisms in the host signaling response to coxsackievirus B3 infection
Pairwise network mechanisms in the host signaling response to coxsackievirus B3 infection
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DOI：
10.1073/pnas.1006478107
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发表时间：
2010-09-28
影响因子：
11.1
通讯作者：
McManus, Bruce M.
中科院分区：
文献类型：
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作者：
Garmaroudi, Farshid S.;Marchant, David;McManus, Bruce M.
信号转导网络可以被生物化学、遗传学和生物化学扰乱，以解开它们的功能。但在系统层面，目前尚不清楚如何最好地实施这种扰动，以提取网络功能的分子机制。在这里，我们结合成对扰动与多参数磷酸化测量，以揭示心肌细胞对柯萨奇病毒B3（CVB 3）感染的信号网络反应中的因果机制。使用所有可能的对6激酶抑制剂，我们组装了一个动态的9蛋白磷酸化的干扰CVB 3感染性的签名。对所得数据集的聚类分析反复表明，配对抑制剂数据是准确预测宿主网络中激酶底物链接的数据驱动预测所必需的。利用成对数据，我们还基于偏相关性推导出了一个高置信度网络，该网络将磷酸-I κ B α鉴定为测量的磷酸化特征中的中心“枢纽”。重建的网络有助于连接磷酸-I κ B α与宿主细胞中涉及促炎细胞因子TNF和IL-1的自分泌反馈回路。自分泌阻断实质上抑制CVB 3子代的释放和提高宿主细胞的活力，暗示TNF和IL-1作为CVB 3诱导的心肌损伤的细胞自主成分。我们的结论是，成对的扰动，当与网络水平的细胞内测量相结合，丰富的机制，将被忽视的单一扰动。
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 multiparameter 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-I kappa B alpha as a central "hub" in the measured phosphorylation signature. The reconstructed network helped to connect phospho-I kappa B alpha 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.