Naz Anam, Obaid Ayesha, Awan Faryal M, Ikram Aqsa, Ahmad Jamil, Ali Amjad
Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and TechnologyIslamabad, Pakistan.
Research Center for Modeling & Simulation, National University of Sciences and TechnologyIslamabad, Pakistan.
Front Microbiol. 2017 Sep 6;8:1682. doi: 10.3389/fmicb.2017.01682. eCollection 2017.
Tight junctions help prevent the passage of digestive enzymes and microorganisms through the space between adjacent epithelial cells lining. However, encoded virulence factors negatively regulate these tight junctions and contribute to dysfunction of gastric mucosa. Here, we have predicted the regulation of important tight junction proteins, such as Zonula occludens-1, Claudin-2 and Connexin32 in the presence of pathogenic proteins. Molecular events such as post translational modifications and crosstalk between phosphorylation, O-glycosylation, palmitoylation and methylation are explored which may compromise the integrity of these tight junction proteins. Furthermore, the signaling pathways disrupted by dysregulated kinases, proteins and post-translational modifications are reviewed to design an abstracted computational model showing the situation-dependent dynamic behaviors of these biological processes and entities. A qualitative hybrid Petri Net model is therefore constructed showing the altered host pathways in the presence of virulence factor cytotoxin-associated gene A, leading to the disruption of tight junction proteins. The model is qualitative logic-based, which does not depend on any kinetic parameter and quantitative data and depends on knowledge derived from experiments. The designed model provides insights into the tight junction disruption and disease progression. Model is then verified by the available experimental data, nevertheless formal experimentation is a promising way to ensure its validation. The major findings propose that activated kinases are responsible to trigger specific post translational modifications within tight junction proteins, at specific sites. These modifications may favor alterations in gastric barrier and provide a route to bacterial invasion into host cells.
紧密连接有助于防止消化酶和微生物通过相邻上皮细胞内衬之间的间隙。然而，编码的毒力因子会对这些紧密连接产生负调控，并导致胃黏膜功能障碍。在此，我们预测了在致病蛋白存在的情况下，重要紧密连接蛋白如闭合蛋白-1、紧密连接蛋白-2和连接蛋白32的调控情况。我们探索了诸如翻译后修饰以及磷酸化、O-糖基化、棕榈酰化和甲基化之间的相互作用等分子事件，这些事件可能会损害这些紧密连接蛋白的完整性。此外，我们还综述了因激酶、蛋白质和翻译后修饰失调而被破坏的信号通路，以设计一个抽象的计算模型，展示这些生物过程和实体在不同情况下的动态行为。因此，构建了一个定性混合Petri网模型，该模型显示了在毒力因子细胞毒素相关基因A存在的情况下宿主通路的改变，导致紧密连接蛋白的破坏。该模型基于定性逻辑，不依赖于任何动力学参数和定量数据，而是依赖于从实验中获得的知识。所设计的模型为紧密连接破坏和疾病进展提供了见解。然后，该模型通过现有的实验数据进行了验证，不过形式化实验是确保其有效性的一种很有前景的方法。主要研究结果表明，激活的激酶负责在紧密连接蛋白的特定位点触发特定的翻译后修饰。这些修饰可能有利于胃屏障的改变，并为细菌侵入宿主细胞提供一条途径。
