Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNα) orchestrates antiviral responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNα doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNα signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model‐based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNα dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNα leads to a dose‐dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient‐specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient‐specific pathway desensitization, while the abundance of STAT2 predicts the patient‐specific IFNα signal response.

中文翻译：

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解开调节干扰素α信号转导敏化的分子机制。

紧密相连的反馈调节器控制信号转导途径激活引起的细胞内反应的动态。干扰素 α (IFNα) 在肝细胞中协调抗病毒反应，但定义响应不同 IFNα 剂量预刺激的通路致敏的机制仍未解决。我们根据肝癌细胞系 Huh7.5 获得的定量测量结果，建立了 IFNα 信号转导的常微分方程模型，其中包括反馈调节器 STAT1、STAT2、IRF9、USP18、SOCS1、SOCS3 和 IRF2。基于模型的分析表明，在信号蛋白 STAT2 和 IRF9 的介导下，低 IFNα 剂量的预刺激会使该通路变得超敏。相反，用高剂量 IFNα 预刺激会导致剂量依赖性脱敏，这是由作用于受体的负调节因子 USP18 和 SOCS1 介导的。对原代人肝细胞中基础蛋白丰度的分析揭示了患者特异性 STAT1、STAT2、IRF9 和 USP18 含量的高度异质性。数学模型方法表明，USP18 的基础量决定患者特异性通路脱敏，而 STAT2 的丰度则预测患者特异性 IFNα 信号反应。