Department of Infectious Diseases, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
J Virol. 2022 Sep 14;96(17):e0077422. doi: 10.1128/jvi.00774-22. Epub 2022 Aug 16.
XIAP-associated factor 1 (XAF1) is an interferon (IFN)-stimulated gene (ISG) that enhances IFN-induced apoptosis. However, it is unexplored whether XAF1 is essential for the host fighting against invaded viruses. Here, we find that XAF1 is significantly upregulated in the host cells infected with emerging RNA viruses, including influenza, Zika virus (ZIKV), and SARS-CoV-2. IFN regulatory factor 1 (IRF1), a key transcription factor in immune cells, determines the induction of XAF1 during antiviral immunity. Ectopic expression of XAF1 protects host cells against various RNA viruses independent of apoptosis. Knockout of XAF1 attenuates host antiviral innate immunity and , which leads to more severe lung injuries and higher mortality in the influenza infection mouse model. XAF1 stabilizes IRF1 protein by antagonizing the CHIP-mediated degradation of IRF1, thus inducing more antiviral IRF1 target genes, including , , , and . Our study has described a protective role of XAF1 in the host antiviral innate immunity against RNA viruses. We have also elucidated the molecular mechanism that IRF1 and XAF1 form a positive feedback loop to induce rapid and robust antiviral immunity. Rapid and robust induction of antiviral genes is essential for the host to clear the invaded viruses. In addition to the IRF3/7-IFN-I-STAT1 signaling axis, the XAF1-IRF1 positive feedback loop synergistically or independently drives the transcription of antiviral genes. Moreover, XAF1 is a sensitive and reliable gene that positively correlates with the viral infection, suggesting that XAF1 is a potential diagnostic marker for viral infectious diseases. In addition to the antitumor role, our study has shown that XAF1 is essential for antiviral immunity. XAF1 is not only a proapoptotic ISG, but it also stabilizes the master transcription factor IRF1 to induce antiviral genes. IRF1 directly binds to the IRF-Es of its target gene promoters and drives their transcriptions, which suggests a unique role of the XAF1-IRF1 loop in antiviral innate immunity, particularly in the host defect of IFN-I signaling such as invertebrates.
XIAP 相关因子 1（XAF1）是一种干扰素（IFN）刺激基因（ISG），可增强 IFN 诱导的细胞凋亡。然而，目前尚不清楚 XAF1 是否对宿主抵抗入侵病毒至关重要。在这里，我们发现，在感染新兴 RNA 病毒（包括流感病毒、寨卡病毒（ZIKV）和 SARS-CoV-2）的宿主细胞中，XAF1 显著上调。IRF1，免疫细胞中的关键转录因子，决定了抗病毒免疫过程中 XAF1 的诱导。XAF1 的异位表达可独立于细胞凋亡保护宿主细胞免受各种 RNA 病毒的侵害。XAF1 的敲除会减弱宿主抗病毒固有免疫，导致流感感染小鼠模型中的肺部损伤更严重，死亡率更高。XAF1 通过拮抗 CHIP 介导的 IRF1 降解来稳定 IRF1 蛋白，从而诱导更多抗病毒的 IRF1 靶基因，包括 、 、 和 。我们的研究描述了 XAF1 在宿主抗病毒固有免疫中对 RNA 病毒的保护作用。我们还阐明了分子机制，即 IRF1 和 XAF1 形成正反馈环，以诱导快速而强大的抗病毒免疫。快速而强大的诱导抗病毒基因对于宿主清除入侵病毒至关重要。除了 IRF3/7-IFN-I-STAT1 信号轴之外，XAF1-IRF1 正反馈环协同或独立地驱动抗病毒基因的转录。此外，XAF1 是一个敏感且可靠的基因，与病毒感染呈正相关，提示 XAF1 可能是病毒感染性疾病的潜在诊断标志物。除了抗肿瘤作用外，我们的研究还表明，XAF1 对抗病毒免疫至关重要。XAF1 不仅是一个促凋亡的 ISG，而且还稳定了主转录因子 IRF1 以诱导抗病毒基因。IRF1 直接结合其靶基因启动子的 IRF-Es 并驱动其转录，这表明 XAF1-IRF1 环在抗病毒固有免疫中具有独特作用，特别是在 IFN-I 信号转导宿主缺陷（如无脊椎动物）的情况下。
