The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is one of the most important transcription factors involved in the regulation of inflammatory signaling pathways. Inappropriate activation of these pathways has been linked to autoimmunity and cancers. Emerging experimental evidences have been showing the existence of elaborate spatial organizations for various molecular components in the pathways. One example is the scaffold protein tumor necrosis factor receptor associated factor (TRAF). While most TRAF proteins form trimeric quaternary structure through their coiled-coil regions, the N-terminal region of some members in the family can further be dimerized. This dimerization of TRAF trimers can drive them into higher-order clusters as a response to receptor stimulation, which functions as a spatial platform to mediate the downstream poly-ubiquitination. However, the molecular mechanism underlying the TRAF protein clustering and its functional impacts are not well-understood. In this article, we developed a hybrid simulation method to tackle this problem. The assembly of TRAF-based signaling platform at the membrane-proximal region is modeled with spatial resolution, while the dynamics of downstream signaling network, including the negative feedbacks through various signaling inhibitors, is simulated as stochastic chemical reactions. These two algorithms are further synchronized under a multiscale simulation framework. Using this computational model, we illustrated that the formation of TRAF signaling platform can trigger an oscillatory NF-κB response. We further demonstrated that the temporal patterns of downstream signal oscillations are closely regulated by the spatial factors of TRAF clustering, such as the geometry and energy of dimerization between TRAF trimers. In general, our study sheds light on the basic mechanism of NF-κB signaling pathway and highlights the functional importance of spatial regulation within the pathway. The simulation framework also showcases its potential of application to other signaling pathways in cells.

中文翻译：

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通过混合模拟对 NF-κB 信号通路中的空间组织进行机械剖析

活化 B 细胞的核因子 kappa-轻链增强子 (NF-κB) 是参与调节炎症信号通路的最重要的转录因子之一。这些途径的不适当激活与自身免疫和癌症有关。新出现的实验证据表明，通路中存在各种分子成分的精细空间组织。一个例子是支架蛋白肿瘤坏死因子受体相关因子（TRAF）。虽然大多数 TRAF 蛋白通过其卷曲螺旋区域形成三聚体四级结构，但该家族中一些成员的 N 末端区域可以进一步二聚化。TRAF 三聚体的这种二聚化可以驱动它们进入更高阶的簇，作为对受体刺激的反应，它作为一个空间平台来介导下游的多泛素化。然而，TRAF 蛋白聚集及其功能影响的分子机制尚不清楚。在本文中，我们开发了一种混合仿真方法来解决这个问题。基于TRAF的信号平台在膜近端区域的组装以空间分辨率建模，而下游信号网络的动力学，包括通过各种信号抑制剂的负反馈，被模拟为随机化学反应。这两种算法在多尺度仿真框架下进一步同步。使用这种计算模型，我们说明了 TRAF 信号平台的形成可以触发振荡的 NF-κB 反应。我们进一步证明了下游信号振荡的时间模式受到 TRAF 聚类的空间因素的密切调节，例如 TRAF 三聚体之间二聚体的几何形状和能量。总的来说，我们的研究阐明了 NF-κB 信号通路的基本机制，并强调了该通路内空间调节的功能重要性。该模拟框架还展示了其应用于细胞中其他信号通路的潜力。