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首页> 外文期刊>PLoS Computational Biology >STL-based Analysis of TRAIL-induced Apoptosis Challenges the Notion of Type I/Type II Cell Line Classification
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STL-based Analysis of TRAIL-induced Apoptosis Challenges the Notion of Type I/Type II Cell Line Classification

机译：基于STL的诱导细胞凋亡分析挑战I / II型细胞系分类的概念

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Extrinsic apoptosis is a programmed cell death triggered by external ligands, such as the TNF-related apoptosis inducing ligand (TRAIL). Depending on the cell line, the specific molecular mechanisms leading to cell death may significantly differ. Precise characterization of these differences is crucial for understanding and exploiting extrinsic apoptosis. Cells show distinct behaviors on several aspects of apoptosis, including (i) the relative order of caspases activation, (ii) the necessity of mitochondria outer membrane permeabilization (MOMP) for effector caspase activation, and (iii) the survival of cell lines overexpressing Bcl2. These differences are attributed to the activation of one of two pathways, leading to classification of cell lines into two groups: type I and type II. In this work we challenge this type I/type II cell line classification. We encode the three aforementioned distinguishing behaviors in a formal language, called signal temporal logic (STL), and use it to extensively test the validity of a previously-proposed model of TRAIL-induced apoptosis with respect to experimental observations made on different cell lines. After having solved a few inconsistencies using STL-guided parameter search, we show that these three criteria do not define consistent cell line classifications in type I or type II, and suggest mutants that are predicted to exhibit ambivalent behaviors. In particular, this finding sheds light on the role of a feedback loop between caspases, and reconciliates two apparently-conflicting views regarding the importance of either upstream or downstream processes for cell-type determination. More generally, our work suggests that these three distinguishing behaviors should be merely considered as type I/II features rather than cell-type defining criteria. On the methodological side, this work illustrates the biological relevance of STL-diagrams, STL population data, and STL-guided parameter search implemented in the tool Breach. Such tools are well-adapted to the ever-increasing availability of heterogeneous knowledge on complex signal transduction pathways.
机译：外部细胞凋亡是由外部配体引发的编程细胞死亡，例如与TNF相关的凋亡诱导配体（TRAIL）。根据细胞系，导致细胞死亡的特定分子机制可能会显着不同。这些差异的精确表征对于理解和利用外在凋亡至关重要。细胞显示出在细胞凋亡的几个方面的不同行为，包括（i）胱天冬酶激活的相对顺序，（ii）用于效应胱天冬酶活化的线粒体外膜透化（MOMP）的必要性，（iii）过表达BCL2的细胞系的存活率。这些差异归因于两个途径中的一个，导致细胞系分为两组：I型和II型。在这项工作中，我们挑战这种类型I / II型细胞系分类。我们以正式的语言编码三个上述区别的行为，称为信号时间逻辑（STL），并使用它来广泛测试关于在不同细胞系上制作的实验观察结果的先前提出的诱导细胞凋亡模型的有效性。在解决了一些使用STL-Guided参数搜索的不一致之后，我们表明这三个标准没有定义I型或II型的一致细胞系分类，并建议预测展示矛盾行为的突变体。特别是，该发现揭示了落下了基础酶之间的反馈环路的作用，并对关于细胞类型确定的上游或下游过程的重要性和解两个明显相互冲突的视图。更一般地，我们的工作表明，这三种区别行为仅被视为I / II型特征，而不是细胞类型定义标准。在方法方面，这项工作说明了在工具破坏中实现的STL图，STL群体数据和STL-Guided参数搜索的生物学相关性。这些工具很好地适应了对复杂信号转导途径的异质知识的不断增加的可用性。

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