Rhodes David M, Smith Sarah A, Holcombe Mike, Qwarnstrom Eva E
Department of Cardiovascular Science, Medical School, University of Sheffield, United Kingdom; Department of Computer Science, University of Sheffield, Sheffield, United Kingdom.
Department of Cardiovascular Science, Medical School, University of Sheffield, United Kingdom.
PLoS One. 2015 Jun 25;10(6):e0129888. doi: 10.1371/journal.pone.0129888. eCollection 2015.
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.
转录因子NF-κB（核因子κB）可被Toll样受体激活，并受机械转导和细胞骨架变化的调控。在本研究中，我们将三维预测蛋白质建模、体外实验与计算机模拟相结合，以确定细胞骨架在NF-κB调控中的作用。模拟使用了基于主体的NF-κB信号通路综合模型，该模型包括1型白细胞介素-1受体（IL-1R1）复合物和信号中间体，以及细胞骨架成分。基于主体的建模依赖于系统组件间相互作用的计算机模拟再现，并为研究需要空间考虑且涉及调控组件复杂形成和转运的生物过程提供了可靠工具。我们表明，我们的模型忠实地再现了构成NF-κB信号通路的多个步骤，并提供了一个框架，从中我们可以探索该系统的新方面。使用三维预测蛋白质建模和体外实验的分析表明，NF-κB抑制剂IκBα在静息细胞的细胞骨架内被隔离在肌动蛋白/血影蛋白复合物中，并在白细胞介素-1刺激期间通过白细胞介素-1受体辅助受体TILRR（Toll样和白细胞介素-1受体调节剂）控制的过程释放。使用基于主体模型的计算机模拟预测，IκBα的细胞骨架池被释放以根据输入水平调整信号放大。结果表明，该过程提供了一种信号校准机制，并能够对NF-κB和炎症反应进行高效的、激活敏感的调控。
