Mertins Philipp, Przybylski Dariusz, Yosef Nir, Qiao Jana, Clauser Karl, Raychowdhury Raktima, Eisenhaure Thomas M, Maritzen Tanja, Haucke Volker, Satoh Takashi, Akira Shizuo, Carr Steven A, Regev Aviv, Hacohen Nir, Chevrier Nicolas
Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA.
Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Electrical Engineering and Computer Science and Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
Cell Rep. 2017 Jun 27;19(13):2853-2866. doi: 10.1016/j.celrep.2017.06.016.
Building an integrated view of cellular responses to environmental cues remains a fundamental challenge due to the complexity of intracellular networks in mammalian cells. Here, we introduce an integrative biochemical and genetic framework to dissect signal transduction events using multiple data types and, in particular, to unify signaling and transcriptional networks. Using the Toll-like receptor (TLR) system as a model cellular response, we generate multifaceted datasets on physical, enzymatic, and functional interactions and integrate these data to reveal biochemical paths that connect TLR4 signaling to transcription. We define the roles of proximal TLR4 kinases, identify and functionally test two dozen candidate regulators, and demonstrate a role for Ap1ar (encoding the Gadkin protein) and its binding partner, Picalm, potentially linking vesicle transport with pro-inflammatory responses. Our study thus demonstrates how deciphering dynamic cellular responses by integrating datasets on various regulatory layers defines key components and higher-order logic underlying signaling-to-transcription pathways.
由于哺乳动物细胞内网络的复杂性，构建细胞对环境信号反应的综合视图仍然是一项根本性挑战。在此，我们引入了一个综合的生化和遗传框架，以利用多种数据类型剖析信号转导事件，特别是统一信号传导和转录网络。以Toll样受体（TLR）系统作为细胞反应模型，我们生成了关于物理、酶促和功能相互作用的多方面数据集，并整合这些数据以揭示将TLR4信号传导与转录联系起来的生化途径。我们确定了近端TLR4激酶的作用，鉴定并对二十多个候选调节因子进行了功能测试，并证明了Ap1ar（编码Gadkin蛋白）及其结合伴侣Picalm的作用，它们可能将囊泡运输与促炎反应联系起来。因此，我们的研究展示了通过整合不同调节层面的数据集来解读动态细胞反应如何定义信号转导至转录途径的关键成分和高阶逻辑。
