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I 型和 II 型干扰素激活 cGAS-STING-IRF3 轴有助于宿主防御。

Activation of the cGAS-STING-IRF3 Axis by Type I and II Interferons Contributes to Host Defense.

机构信息

Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.

University of Chinese Academy of Sciences, Bejing, 100049, China.

出版信息

Adv Sci (Weinh). 2024 Sep;11(35):e2308890. doi: 10.1002/advs.202308890. Epub 2024 Jul 14.

DOI:10.1002/advs.202308890
PMID:39004913
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11425201/
Abstract

Interferons (IFNs) activate JAK-STAT pathways to induce downstream effector genes for host defense against invaded pathogens and tumors. Here both type I (β) and II (γ) IFNs are shown that can activate the transcription factor IRF3 in parallel with STAT1. IRF3-deficiency impairs transcription of a subset of downstream effector genes induced by IFN-β and IFN-γ. Mechanistically, IFN-induced activation of IRF3 is dependent on the cGAS-STING-TBK1 axis. Both IFN-β and IFN-γ cause mitochondrial DNA release into the cytosol. In addition, IFNs induce JAK1-mediated tyrosine phosphorylation of cGAS at Y214/Y215, which is essential for its DNA binding activity and signaling. Furthermore, deficiency of cGAS, STING, or IRF3 impairs IFN-β- or IFN-γ-mediated antiviral and antitumor activities. The findings reveal a novel IRF3 activation pathway parallel with the canonical STAT1/2 activation pathways triggered by IFNs and provide an explanation for the pleiotropic roles of the cGAS-STING-IRF3 axis in host defense.

摘要

干扰素 (IFNs) 通过激活 JAK-STAT 途径诱导下游效应基因，以抵抗入侵的病原体和肿瘤。本研究表明，I 型 (β) 和 II 型 (γ) IFN 均可与 STAT1 平行激活转录因子 IRF3。IRF3 缺陷会损害 IFN-β 和 IFN-γ 诱导的下游效应基因的转录。从机制上讲，IFN 诱导的 IRF3 激活依赖于 cGAS-STING-TBK1 轴。IFN-β 和 IFN-γ 均可引起线粒体 DNA 释放到细胞质中。此外，IFNs 诱导 JAK1 介导的 cGAS 酪氨酸磷酸化，在 Y214/Y215 位点磷酸化，这对其 DNA 结合活性和信号转导至关重要。此外，cGAS、STING 或 IRF3 的缺失会损害 IFN-β 或 IFN-γ 介导的抗病毒和抗肿瘤活性。这些发现揭示了一条新的 IRF3 激活途径，与 IFN 触发的经典 STAT1/2 激活途径平行，并为 cGAS-STING-IRF3 轴在宿主防御中的多效性作用提供了解释。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c04e/11425201/f64c3bcdc685/ADVS-11-2308890-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c04e/11425201/6f6b34e54a33/ADVS-11-2308890-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c04e/11425201/f64c3bcdc685/ADVS-11-2308890-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c04e/11425201/2f32a303d486/ADVS-11-2308890-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c04e/11425201/60aa784993b8/ADVS-11-2308890-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c04e/11425201/f64c3bcdc685/ADVS-11-2308890-g002.jpg

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