非自身 RNA 重构了 IFN-β 信号转导：先天性免疫反应的数学模型

IF 6.7 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling Pub Date : 2023-12-12 DOI:10.1126/scisignal.abq1173

Zbigniew Korwek, Maciej Czerkies, Joanna Jaruszewicz-Błońska, Wiktor Prus, Ilona Kosiuk, Marek Kochańczyk, Tomasz Lipniacki

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引用次数: 0

摘要

I型干扰素（IFNs）是先天性免疫对病毒感染反应的关键协调因子，它通过激活旁观者细胞中的转录调节因子STAT1和STAT2（STAT1/2），诱导IFN刺激基因（ISGs）的表达。在这里，我们发现在转染了病毒 RNA 类似物 poly(I:C) 的细胞中，由于干扰素-β（IFN-β）受体 IFNAR 的耗竭，STAT1/2 的转录活性被终止。两种 ISGs 的产物 RNase L 和 PKR 的激活不仅阻碍了 IFNAR 的补充，还抑制了 IRF3 和 NF-κB 的负调控因子，从而促进了 IFNB 的转录。我们将这些发现纳入了先天性免疫的数学模型。通过将IRF3-NF-κB和STAT1/2途径的信号传递与RNase L和PKR的活性结合起来，该模型解释了poly(I:C)如何将转录程序从STAT1/2诱导转换为IRF3和NF-κB诱导，从而将IFN-β应答细胞转换为IFN-β分泌细胞。

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Nonself RNA rewires IFN-β signaling: A mathematical model of the innate immune response

Type I interferons (IFNs) are key coordinators of the innate immune response to viral infection, which, through activation of the transcriptional regulators STAT1 and STAT2 (STAT1/2) in bystander cells, induce the expression of IFN-stimulated genes (ISGs). Here, we showed that in cells transfected with poly(I:C), an analog of viral RNA, the transcriptional activity of STAT1/2 was terminated because of depletion of the interferon-β (IFN-β) receptor, IFNAR. Activation of RNase L and PKR, products of two ISGs, not only hindered the replenishment of IFNAR but also suppressed negative regulators of IRF3 and NF-κB, consequently promoting IFNB transcription. We incorporated these findings into a mathematical model of innate immunity. By coupling signaling through the IRF3–NF-κB and STAT1/2 pathways with the activities of RNase L and PKR, the model explains how poly(I:C) switches the transcriptional program from being STAT1/2 induced to being IRF3 and NF-κB induced, which converts IFN-β–responding cells to IFN-β–secreting cells.

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来源期刊

Science Signaling BIOCHEMISTRY & MOLECULAR BIOLOGY-CELL BIOLOGY

CiteScore

9.50

自引率

0.00%

发文量

148

审稿时长

3-8 weeks

期刊介绍： "Science Signaling" is a reputable, peer-reviewed journal dedicated to the exploration of cell communication mechanisms, offering a comprehensive view of the intricate processes that govern cellular regulation. This journal, published weekly online by the American Association for the Advancement of Science (AAAS), is a go-to resource for the latest research in cell signaling and its various facets. The journal's scope encompasses a broad range of topics, including the study of signaling networks, synthetic biology, systems biology, and the application of these findings in drug discovery. It also delves into the computational and modeling aspects of regulatory pathways, providing insights into how cells communicate and respond to their environment. In addition to publishing full-length articles that report on groundbreaking research, "Science Signaling" also features reviews that synthesize current knowledge in the field, focus articles that highlight specific areas of interest, and editor-written highlights that draw attention to particularly significant studies. This mix of content ensures that the journal serves as a valuable resource for both researchers and professionals looking to stay abreast of the latest advancements in cell communication science.