Determinants of Ligand Specificity and Functional Plasticity in Type I Interferon Signaling.
Determinants of Ligand Specificity and Functional Plasticity in Type I Interferon Signaling.
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DOI：
10.3389/fimmu.2021.748423
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发表时间：
2021
影响因子：
7.3
通讯作者：
Zilman A
中科院分区：
文献类型：
--
作者：
Kirby D;Parmar B;Fathi S;Marwah S;Nayak CR;Cherepanov V;MacParland S;Feld JJ;Altan-Bonnet G;Zilman A
细胞因子的I型干扰素家族都通过相同的细胞表面受体起作用，并诱导STAT家族的相同亚组的反应调节剂的磷酸化。尽管它们共享受体，但不同的I型干扰素在对感染的免疫应答期间具有不同的功能。特别是，它们在靶细胞中诱导的抗病毒和抗增殖应答的效力不同。这些功能差异如何以配体特异性的方式在STAT磷酸化水平和下游功能上产生，目前还没有完全了解。我们使用I型干扰素信号传导的最小计算模型，重点是干扰素-α和干扰素-β。我们用定量实验数据验证了该模型，以确定I型干扰素信号传导中特异性和功能可塑性的关键决定因素。我们研究了不同的信号识别机制，以及多个系统组件，如结合亲和力，受体表达水平及其变异性，受体内化，SOCS 1蛋白的短期负反馈和差异受体表达如何共同发挥作用，以确保STAT磷酸化水平上的配体特异性。基于这些结果，我们提出了从STAT激活到下游抗病毒和抗增殖活性的现象学功能映射，以研究STAT磷酸化下游的差异信号处理步骤。我们发现蛋白USP 18的负反馈通过配体依赖性不应性增强干扰素之间的信号传导差异，可以引起干扰素-α和干扰素-β信号传导的功能可塑性，并探索控制功能可塑性的其他因素。除了I型干扰素信号传导，我们的研究结果具有广泛的适用性，信号传导系统的信号特异性和功能可塑性的问题，多个配体通过一个瓶颈的少数共享受体。
The Type I Interferon family of cytokines all act through the same cell surface receptor and induce phosphorylation of the same subset of response regulators of the STAT family. Despite their shared receptor, different Type I Interferons have different functions during immune response to infection. In particular, they differ in the potency of their induced anti-viral and anti-proliferative responses in target cells. It remains not fully understood how these functional differences can arise in a ligand-specific manner both at the level of STAT phosphorylation and the downstream function. We use a minimal computational model of Type I Interferon signaling, focusing on Interferon-α and Interferon-β. We validate the model with quantitative experimental data to identify the key determinants of specificity and functional plasticity in Type I Interferon signaling. We investigate different mechanisms of signal discrimination, and how multiple system components such as binding affinity, receptor expression levels and their variability, receptor internalization, short-term negative feedback by SOCS1 protein, and differential receptor expression play together to ensure ligand specificity on the level of STAT phosphorylation. Based on these results, we propose phenomenological functional mappings from STAT activation to downstream anti-viral and anti-proliferative activity to investigate differential signal processing steps downstream of STAT phosphorylation. We find that the negative feedback by the protein USP18, which enhances differences in signaling between Interferons via ligand-dependent refractoriness, can give rise to functional plasticity in Interferon-α and Interferon-β signaling, and explore other factors that control functional plasticity. Beyond Type I Interferon signaling, our results have a broad applicability to questions of signaling specificity and functional plasticity in signaling systems with multiple ligands acting through a bottleneck of a small number of shared receptors.