Cells use sophisticated molecular circuits to interpret and respond to extracellular signal factors, such as hormones and cytokines, which are often released in a temporally varying fashion. In this study, we focus on type I interferon (IFN) signaling in human epithelial cells and combine microfluidics, time-lapse microscopy, and computational modeling to investigate how the IFN-responsive regulatory network operates in single cells to process repetitive IFN stimulation. We found that IFN-α pretreatments lead to opposite effects, priming versus desensitization, depending on the 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 and 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 control processes, enabling duration-dependent desensitization to repetitive stimulations. Moreover, our results, highlighting the importance of IFN dynamics, may suggest time-based strategies for enhancing the effectiveness of IFN pretreatment in clinical applications against viruses, such as SARS-CoV-2.

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

细胞使用复杂的分子回路来解释和响应通常以时变方式释放的细胞外信号因子，例如激素和细胞因子。在这项研究中，我们专注于人上皮细胞中的I型干扰素（IFN）信号传导，并结合微流控技术，延时显微镜和计算模型来研究IFN响应性调控网络如何在单细胞中运行以处理重复性IFN刺激。我们发现，根据输入持续时间的不同，IFN-α预处理会产生相反的作用，即引发与脱敏。这些作用受一个由快速作用的正反馈回路和延迟的负反馈回路组成的调节网络控制，该调节网络由泛素特异性肽酶18（USP18）的上调介导。我们进一步揭示，USP18上调只能在治疗开始后在细胞周期的G1期和早期S期开始，从而导致单细胞异质性和延迟的诱导动力学。这种细胞周期门控提供了反馈控制过程的时间分隔，从而使对重复刺激的持续时间依赖于脱敏。此外，我们的研究结果突显了IFN动力学的重要性，可能会提出基于时间的策略，以增强IFN预处理在临床应用中针对病毒（如SARS-CoV-2）的有效性。可以对重复刺激进行持续时间依赖性的脱敏。此外，我们的研究结果突显了IFN动力学的重要性，可能会提出基于时间的策略，以增强IFN预处理在临床应用中针对病毒（如SARS-CoV-2）的有效性。可以对重复刺激进行持续时间依赖性的脱敏。此外，我们的研究结果突显了IFN动力学的重要性，可能会提出基于时间的策略，以增强IFN预处理在临床应用中针对病毒（如SARS-CoV-2）的有效性。