Cells use molecular circuits to interpret and respond to extracellular cues, such as hormones and cytokines, which are often released in a temporally varying fashion. In this study, we combine microfluidics, time-lapse microscopy, and computational modeling to investigate how the type I interferon (IFN)-responsive regulatory network operates in single human cells to process repetitive IFN stimulation. We found that IFN-α pretreatments lead to opposite effects, priming versus desensitization, depending on input durations. These effects are governed by a regulatory network composed of a fast-acting positive feedback loop and a delayed negative feedback loop, mediated by upregulation of ubiquitin-specific peptidase 18 (USP18). We further revealed that USP18 upregulation can only be initiated at the G1/early S phases of cell cycle upon the treatment onset, resulting in heterogeneous and delayed induction kinetics in single cells. This cell cycle gating provides a temporal compartmentalization of feedback loops, enabling duration-dependent desensitization to repetitive stimulations.

中文翻译：

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细胞周期门控反馈控制介导对干扰素刺激的脱敏

细胞使用分子回路来解释和响应细胞外信号，例如激素和细胞因子，它们通常以随时间变化的方式释放。在这项研究中，我们结合微流体、延时显微镜和计算模型来研究 I 型干扰素 (IFN) 响应调节网络如何在单个人类细胞中运作以处理重复的 IFN 刺激。我们发现 IFN-α 预处理会导致相反的效果，即启动与脱敏，具体取决于输入持续时间。这些效应由一个调节网络控制，该网络由一个快速作用的正反馈回路和一个延迟的负反馈回路组成，由泛素特异性肽酶 18 (USP18) 的上调介导。我们进一步揭示，USP18 上调只能在治疗开始时在细胞周期的 G1/S 早期开始，导致单细胞中的异质和延迟诱导动力学。这种细胞周期门控提供了反馈回路的时间划分，使对重复刺激的持续时间依赖性脱敏成为可能。