Distinct single-cell signaling characteristics are conferred by the MyD88 and TRIF pathways during TLR4 activation.
Distinct single-cell signaling characteristics are conferred by the MyD88 and TRIF pathways during TLR4 activation.
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DOI：
10.1126/scisignal.aaa5208
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发表时间：
2015-07-14
影响因子：
7.3
通讯作者：
Hoffmann A
中科院分区：
文献类型：
--
作者：
Cheng Z;Taylor B;Ourthiague DR;Hoffmann A
Toll样受体（TLR）识别特定病原体相关的分子模式，并通过依赖于衔接蛋白MyD 88（髓样分化标记物88）或TRIF（含TIR结构域的衔接蛋白诱导干扰素-β）的信号传导途径启动先天性免疫应答。特别是TLR 4，使用两种接头蛋白来激活转录因子核因子κB（NF-κB）;然而，这两种途径的特异性和冗余性仍有待阐明。我们开发了一个数学模型，以显示每个途径如何编码NF-κB活性的不同动力学特征，并对单细胞测量中观察到的高变异性做出不同的贡献。与细胞表面受体相关的MyD 88周围大分子信号平台的组装决定了初始反应的时间，以产生可靠的数字NF-κB信号。相比之下，配体诱导的受体内化到核内体中通过TRIF产生嘈杂、延迟但持续的NF-κB信号。通过迭代数学模型的开发，我们预测了MyD 88和TRIF介导的途径提供配体浓度依赖性信号传导动力学的分子机制，这些信号传导动力学传递有关病原体威胁的信息。
Toll-like receptors (TLRs) recognize specific pathogen–associated molecular patterns and initiate innate immune responses through signaling pathways that depend on the adaptor proteins MyD88 (myeloid differentiation marker 88) or TRIF (TIR domain–containing adaptor protein–inducing interferon-β). TLR4, in particular, uses both adaptor proteins to activate the transcription factor nuclear factor κB (nF-κB); however, the specificity and redundancy of these two pathways remain to be elucidated. We developed a mathematical model to show how each pathway encodes distinct dynamical features of NF-κB activity and makes distinct contributions to the high variability observed in single-cell measurements. The assembly of a macromolecular signaling platform around MyD88 associated with receptors at the cell surface determined the timing of initial responses to generate a reliable, digital NF-κB signal. In contrast, ligand-induced receptor internalization into endosomes produced noisy, delayed, yet sustained NF-κB signals through TRIF. With iterative mathematical model development, we predicted the molecular mechanisms by which the MyD88- and TRIF-mediated pathways provide ligand concentration–dependent signaling dynamics that transmit information about the pathogen threat.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
影响因子：
4
作者：
Behar, Marcelo;Hoffmann, Alexander
通讯作者：
Hoffmann, Alexander
影响因子：
4.8
作者：
GEGNER, JA;ULEVITCH, RJ;TOBIAS, PS
通讯作者：
TOBIAS, PS
影响因子：
64.5
作者：
Altschuler SJ;Wu LF
通讯作者：
Wu LF
DOI：
10.1084/jem.20031076
发表时间：
2003-10-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Akashi S;Saitoh S;Wakabayashi Y;Kikuchi T;Takamura N;Nagai Y;Kusumoto Y;Fukase K;Kusumoto S;Adachi Y;Kosugi A;Miyake K
通讯作者：
Miyake K