ZNFX1 antisense RNA1 promotes antiviral innate immune responses via modulating ZNFX1 function
ZNFX1 antisense RNA1 promotes antiviral innate immune responses via modulating ZNFX1 function
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DOI：
10.1002/jmv.28637
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发表时间：
2023-03
影响因子：
12.7
通讯作者：
Xin Jia;Mei-qi Zhang;Haojia Wang;Cui-qin Cheng;Qi-qi Li;Yi-ying Li;Lingdong Kong;Xihong Lan;Yuxi Wang;Xue Liang;Shaochun Yuan;Yao Wang;A. Xu
中科院分区：
文献类型：
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作者：
Xin Jia;Mei-qi Zhang;Haojia Wang;Cui-qin Cheng;Qi-qi Li;Yi-ying Li;Lingdong Kong;Xihong Lan;Yuxi Wang;Xue Liang;Shaochun Yuan;Yao Wang;A. Xu
越来越多的证据表明，天然反义转录 lncRNA 调节其相邻的编码基因以介导生物学的各个方面。对先前鉴定的抗病毒基因 ZNFX1 的生物信息学分析显示，邻近的 lncRNA ZFAS1 转录在 ZNFX1 的相反链上。 ZFAS1 是否通过调节 dsRNA 传感器 ZNFX1 发挥抗病毒功能尚不清楚。在这里，我们发现 ZFAS1 被 RNA 和 DNA 病毒以及 I 型干扰素 (IFN-I) 上调，依赖于 Jak-STAT 信号传导，类似于 ZNFX1 的转录调节。内源性 ZFAS1 的敲低部分促进了病毒感染，而 ZFAS1 过表达则表现出相反的效果。此外，通过输送人 ZFAS1，小鼠对 VSV 感染的抵抗力更强。我们进一步观察到，ZFAS1 敲低显着抑制 IFNB1 表达和 IFR3 二聚化，而 ZFAS1 过表达则正向调节抗病毒先天免疫途径。从机制上讲，ZFAS1通过增强ZNFX1蛋白稳定性，正向调节ZNFX1表达和抗病毒功能，从而建立正反馈环，增强抗病毒免疫激活状态。简而言之，ZFAS1 通过调节其邻近基因 ZNFX1，成为抗病毒先天免疫反应的正调节因子，为先天免疫中 lncRNA 介导的信号调节提供了新的机制见解。
Increasing evidence suggests that natural antisense transcriptional lncRNAs regulate their adjacent coding genes to mediate diverse aspects of biology. Bioinformatics analysis of the previously identified antiviral gene ZNFX1 revealed neighboring lncRNA ZFAS1 transcribed on the opposite strand from ZNFX1. Whether ZFAS1 exerts antiviral function via regulating the dsRNA sensor ZNFX1 is unknown. Here we found that ZFAS1 was upregulated by RNA and DNA viruses and type I IFNs (IFN‐I) dependent on Jak‐STAT signaling, similar to the transcription regulation of ZNFX1. Knockdown of endogenous ZFAS1 partially facilitated viral infection, while ZFAS1 overexpression showed opposite effects. In addition, mice were more resistant to VSV infection with the delivery of human ZFAS1. We further observed that ZFAS1 knockdown significantly inhibited IFNB1 expression and IFR3 dimerization, whereas ZFAS1 overexpression positively regulated antiviral innate immune pathways. Mechanistically, ZFAS1 positively regulated ZNFX1 expression and antiviral function by enhancing the protein stability of ZNFX1, thereby establishing a positive feedback loop to enhance antiviral immune activation status. In short, ZFAS1 is a positive regulator of antiviral innate immune response via regulating its neighbor gene ZNFX1, adding new mechanistic insight into lncRNA‐mediated regulation of signaling in innate immunity.