Integrative Proteomics and Phosphoproteomics Profiling Reveals Dynamic Signaling Networks and Bioenergetics Pathways Underlying T Cell Activation.
Integrative Proteomics and Phosphoproteomics Profiling Reveals Dynamic Signaling Networks and Bioenergetics Pathways Underlying T Cell Activation.
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DOI：
10.1016/j.immuni.2017.02.010
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发表时间：
2017-03-21
期刊：
影响因子：
32.4
通讯作者：
Chi H
中科院分区：
文献类型：
--
作者：
Tan H;Yang K;Li Y;Shaw TI;Wang Y;Blanco DB;Wang X;Cho JH;Wang H;Rankin S;Guy C;Peng J;Chi H
抗原激活静止 T 细胞的分子回路仍知之甚少。我们通过多重同量异位标记蛋白质组学技术、用于整合多组学数据集的计算管道以及功能扰动来结合整个蛋白质组和磷酸化蛋白质组的时间分析，以系统地重建 T 细胞激活的调控网络。 T 细胞受体以离散动力学激活 T 细胞蛋白质组和磷酸化蛋白质组，其特征是磷酸化的早期动力学以及延迟的核糖体生物发生和线粒体激活。系统生物学分析确定了多个功能模块、活性激酶、转录因子及其之间的连接性，以及包括线粒体核糖体和复合体 IV 在内的线粒体途径。遗传扰动揭示了线粒体酶 COX10 介导的氧化磷酸化在 T 细胞静止退出中的生理作用。我们的多层蛋白质组学分析、综合网络分析和功能研究定义了 T 细胞蛋白质组和磷酸化蛋白质组的图谱，并揭示了介导淋巴细胞退出静止状态的信号传导和生物能学途径。
The molecular circuits by which antigens activate quiescent T cells remain poorly understood. We combined temporal profiling of the whole proteome and phosphoproteome via multiplexed isobaric labeling proteomics technology, computational pipelines for integrating multi-omics datasets, and functional perturbation to systemically reconstruct regulatory networks underlying T cell activation. T cell receptors activated the T cell proteome and phosphoproteome with discrete kinetics, marked by early dynamics of phosphorylation and delayed ribosome biogenesis and mitochondrial activation. Systems biology analyses identified multiple functional modules, active kinases, transcription factors and connectivity between them, and mitochondrial pathways including mitoribosomes and complex IV. Genetic perturbation revealed physiological roles for mitochondrial enzyme COX10-mediated oxidative phosphorylation in T cell quiescence exit. Our multi-layer proteomics profiling, integrative network analysis and functional studies define landscapes of the T cell proteome and phosphoproteome and reveal signaling and bioenergetics pathways that mediate lymphocyte exit from quiescence.