Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling
Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling
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DOI：
10.1038/s42003-018-0259-4
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发表时间：
2019-01-18
影响因子：
5.9
通讯作者：
Dittrich, Anna
中科院分区：
文献类型：
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作者：
Billing, Ulrike;Jetka, Tomasz;Dittrich, Anna
通过细胞内信号通路进行的细胞通信至关重要。信号蛋白的表达和激活在同一细胞类型的同基因细胞之间是异质性的。然而，进化的机制使充分的交流成为可能，并确保细胞功能。我们使用信息论来阐明促进IL-6诱导的JAK/STAT信号转导的机制，尽管细胞之间存在差异。我们表明，不同的机制使得对可变性的稳健性是相辅相成的。只要细胞因子浓度较低，STAT3的早期激活就是强劲的。STAT3的高表达或丝氨酸磷酸化确保了在高细胞因子浓度下的稳健性。后来，反馈抑制器SOCS3增加了健壮性。JAK/STAT信号的通道容量受到STAT3表达的细胞间可变性的限制，并受到相同的稳健性控制机制的影响。增加STAT3量可增加通道容量和稳健性，而增加STAT3酪氨酸磷酸化会降低稳健性但增加通道容量。综上所述，我们阐明了尽管细胞间存在异质性，但通过启用可靠的JAK/STAT信号来防止信号失控的机制。
Cellular communication via intracellular signalling pathways is crucial. Expression and activation of signalling proteins is heterogenous between isogenic cells of the same cell-type. However, mechanisms evolved to enable sufficient communication and to ensure cellular functions. We use information theory to clarify mechanisms facilitating IL-6-induced JAK/STAT signalling despite cell-to-cell variability. We show that different mechanisms enabling robustness against variability complement each other. Early STAT3 activation is robust as long as cytokine concentrations are low. Robustness at high cytokine concentrations is ensured by high STAT3 expression or serine phosphorylation. Later the feedback-inhibitor SOCS3 increases robustness. Channel Capacity of JAK/STAT signalling is limited by cell-tocell variability in STAT3 expression and is affected by the same mechanisms governing robustness. Increasing STAT3 amount increases Channel Capacity and robustness, whereas increasing STAT3 tyrosine phosphorylation reduces robustness but increases Channel Capacity. In summary, we elucidate mechanisms preventing dysregulated signalling by enabling reliable JAK/STAT signalling despite cell-to-cell heterogeneity.