Computational Modelling of NF-κB Activation by IL-1RI and Its Co-Receptor TILRR, Predicts a Role for Cytoskeletal Sequestration of IκBα in Inflammatory Signalling.
Computational Modelling of NF-κB Activation by IL-1RI and Its Co-Receptor TILRR, Predicts a Role for Cytoskeletal Sequestration of IκBα in Inflammatory Signalling.
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IL-1RI及其共受体TILRR对NF-κB激活的计算模型预测了IκBα在炎症信号传导中的细胞骨架隔离的作用。
DOI：
10.1371/journal.pone.0129888
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Qwarnstrom EE
中科院分区：
文献类型：
--
作者：
Rhodes DM;Smith SA;Holcombe M;Qwarnstrom EE
转录因子NF-κB（核因子κ B）由Toll样受体激活，并受机械转导和细胞骨架变化的控制。在这项研究中，我们结合联合收割机3-D预测蛋白质建模和体外实验与计算机模拟，以确定细胞骨架在调节NF-κB中的作用。模拟使用了NF-κB通路的全面的基于代理的模型，该模型包括1型IL-1受体（IL-1 R1）复合物和信号传导中间体以及细胞骨架组分。基于代理的建模依赖于通过其组件的相互作用在计算机上复制系统，并提供了一个可靠的工具，在调查的生物过程，这需要空间的考虑，并涉及复杂的形成和易位的监管组件。我们的模型忠实地再现了NF-κB通路的多个步骤，并提供了一个框架，从中我们可以探索系统的新方面。使用3-D预测蛋白质建模和体外分析的分析表明，NF-κB抑制剂IκBα与静息细胞骨架内的肌动蛋白/血影蛋白复合物隔离，并在IL-1刺激期间通过IL-1 RI共受体TILRR（Toll样和IL-1受体调节剂）控制的过程释放。使用基于代理的模型的计算机模拟预测IκBα的细胞骨架池被释放以调节与输入水平相关的信号放大。结果表明，该过程提供了一种信号校准机制，并使NF-κB和炎症反应的有效，活化敏感的调节成为可能。
The transcription factor NF-κB (nuclear factor kappa B) is activated by Toll-like receptors and controlled by mechanotransduction and changes in the cytoskeleton. In this study we combine 3-D predictive protein modelling and in vitro experiments with in silico simulations to determine the role of the cytoskeleton in regulation of NF-κB. Simulations used a comprehensive agent-based model of the NF-κB pathway, which includes the type 1 IL-1 receptor (IL-1R1) complex and signalling intermediates, as well as cytoskeletal components. Agent based modelling relies on in silico reproductions of systems through the interactions of its components, and provides a reliable tool in investigations of biological processes, which require spatial considerations and involve complex formation and translocation of regulatory components. We show that our model faithfully reproduces the multiple steps comprising the NF-κB pathway, and provides a framework from which we can explore novel aspects of the system. The analysis, using 3-D predictive protein modelling and in vitro assays, demonstrated that the NF-κB inhibitor, IκBα is sequestered to the actin/spectrin complex within the cytoskeleton of the resting cell, and released during IL-1 stimulation, through a process controlled by the IL-1RI co-receptor TILRR (Toll-like and IL-1 receptor regulator). In silico simulations using the agent-based model predict that the cytoskeletal pool of IκBα is released to adjust signal amplification in relation to input levels. The results suggest that the process provides a mechanism for signal calibration and enables efficient, activation-sensitive regulation of NF-κB and inflammatory responses.
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影响因子：
14.9
作者：
Tovchigrechko A;Vakser IA
通讯作者：
Vakser IA
DOI：
10.1073/pnas.0510802103
发表时间：
2006-02-21
影响因子：
11.1
作者：
Davis, CN;Mann, E;Bartfai, T
通讯作者：
Bartfai, T
影响因子：
4.8
作者：
Yang, L;Ross, K;Qwarnstrom, EE
通讯作者：
Qwarnstrom, EE
影响因子：
3.3
作者：
Bowe RA;Cox OT;Ayllón V;Tresse E;Healy NC;Edmunds SJ;Huigsloot M;O'Connor R
通讯作者：
O'Connor R
DOI：
10.1126/science.1232251
发表时间：
2013-01-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Xu K;Zhong G;Zhuang X
通讯作者：
Zhuang X