John Kristen, Smith Ethan, Istishin Alexandra, Mahmood Nasif, Diveley Kayleigh, Tollison Tammy S, Carpenter Susan, Peng Xinxia
bioRxiv. 2025 Aug 22:2025.08.18.670784. doi: 10.1101/2025.08.18.670784.
Long noncoding RNAs (lncRNAs) have been found to play significant regulatory roles within antiviral and immune responses. We previously identified the novel lncRNA virus-inducible lncRNA modulator of interferon response ( ), that was found to broadly regulate the host transcriptional response to interferon-beta (IFN-β) treatment in A549 human lung epithelial cells. Here, we investigated the mechanism by which regulates the host interferon response in by identifying interacting proteins and gene regulatory networks of . Through an RNA pull-down assay, we found that interacted with both nuclear and cytoplasmic proteins , including the transcriptional regulators FUBP1 and PUF60 in the nucleus, as well as the antiviral proteins IFIT1 and IFIT3 and the aminoacyl-tRNA synthetases QARS1 and KARS1 in the cytoplasm. In addition, we found that overexpression of in A549 cells resulted in an overall enhancement of host interferon response genes and identified a core set of interferon-stimulated genes that were consistently regulated by knockdown and overexpression. Finally, we proposed several possible mechanisms by which may interact with the identified proteins to regulate the interferon response, such as by interacting with FUBP1 and PUF60 in the nucleus to regulate host transcription in or by interacting with the IFIT proteins and aminoacyl-tRNA synthetases in the cytoplasm to regulate translation.
Despite thousands of long noncoding RNAs (lncRNAs) being differentially expressed after immune responses and viral infections, there is very limited knowledge on their individual functions in these contexts. We previously identified a novel lncRNA, , that was found to be an interferon-stimulated gene that regulated the host transcriptional response to interferon-beta treatment in human epithelial cells. Here, we investigated the mechanism by which regulates the interferon response in . Through studies, we identified several nuclear and cytoplasmic proteins that interact with , including proteins involved in transcriptional and translational regulation. In addition, we demonstrated that the overexpression of results in an enhancement of host interferon response genes, supporting our hypothesis that plays an activating role in the host interferon response. Finally, we propose several potential models for the mechanism of , providing a foundation for the investigation of as a novel therapeutic target in antiviral immunity.
长链非编码RNA（lncRNA）已被发现可在抗病毒和免疫反应中发挥重要调节作用。我们之前鉴定出了新型lncRNA——干扰素反应的病毒诱导性lncRNA调节剂（ ），它被发现可广泛调节A549人肺上皮细胞对干扰素-β（IFN-β）治疗的宿主转录反应。在此，我们通过鉴定 的相互作用蛋白和基因调控网络，研究了 在 中调节宿主干扰素反应的机制。通过RNA下拉实验，我们发现 与细胞核和细胞质蛋白 相互作用，包括细胞核中的转录调节因子FUBP1和PUF60，以及细胞质中的抗病毒蛋白IFIT1和IFIT3，还有氨酰-tRNA合成酶QARS1和KARS1。此外，我们发现A549细胞中 的过表达导致宿主干扰素反应基因整体增强，并鉴定出一组核心的干扰素刺激基因，它们在 敲低和过表达时受到一致调节。最后，我们提出了 可能与已鉴定蛋白相互作用以调节干扰素反应的几种可能机制，例如通过与细胞核中的FUBP1和PUF60相互作用来调节 中的宿主转录，或通过与细胞质中的IFIT蛋白和氨酰-tRNA合成酶相互作用来调节翻译。
尽管在免疫反应和病毒感染后有成千上万的长链非编码RNA（lncRNA）差异表达，但关于它们在这些情况下的个体功能的了解非常有限。我们之前鉴定出一种新型lncRNA， ，它被发现是一种干扰素刺激基因，可调节人上皮细胞对干扰素-β治疗的宿主转录反应。在此，我们研究了 在 中调节干扰素反应的机制。通过 研究，我们鉴定出了几种与 相互作用的细胞核和细胞质蛋白，包括参与转录和翻译调节的蛋白。此外，我们证明 的过表达导致宿主干扰素反应基因增强，支持了我们的假设，即 在宿主干扰素反应中起激活作用。最后，我们提出了 作用机制的几种潜在模型，为将 作为抗病毒免疫中的新型治疗靶点进行研究奠定了基础。
