Institute of Systems Biomedicine, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, P.R. China.
Department of Human Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, P.R. China.
FASEB J. 2022 Aug;36(8):e22409. doi: 10.1096/fj.202200316R.
Interferon regulatory factor 7 (IRF7), as the interferon-stimulated gene, maximally drives type I interferon (IFN) production. However, the mechanisms by which the biological function of IRF7 is regulated remain elusive. In this study, we found that IRF7 selectively interacted with the neuralized E3 ubiquitin-protein ligase 3 (NEURL3). In concomitant with IRF7 induction, NEURL3 is upregulated by NF-κB signaling in the late phase of viral infection. Moreover, NEURL3 augmented the host antiviral immune response through ubiquitinating IRF7. A mechanistic study revealed that NEURL3 triggered K63-linked poly-ubiquitination on IRF7 lysine 375, which in turn epigenetically enhanced the transcription of interferon-stimulated genes (ISGs) through disruption of the association of IRF7 with Histone Deacetylase 1 (HDAC1), consequently augmenting host antiviral immune response. Accordingly, Neurl3 mice produced less type I IFNs and exhibited increased susceptibility to viral infection. Taken together, our findings identify NEURL3 as an E3 ubiquitin ligase of IRF7 and shed new light on the positive regulation of IRF7 in host antiviral immune signaling.
干扰素调节因子 7（IRF7）作为干扰素刺激基因，最大程度地驱动 I 型干扰素（IFN）的产生。然而，IRF7 生物学功能的调节机制仍不清楚。在这项研究中，我们发现 IRF7 选择性地与神经化 E3 泛素蛋白连接酶 3（NEURL3）相互作用。在病毒感染的晚期，NF-κB 信号通路上调了与 IRF7 诱导同时发生的 NEURL3。此外，NEURL3 通过泛素化 IRF7 增强了宿主抗病毒免疫反应。一项机制研究表明，NEURL3 在 IRF7 的赖氨酸 375 上引发 K63 连接的多泛素化，进而通过破坏 IRF7 与组蛋白去乙酰化酶 1（HDAC1）的结合，表观遗传增强干扰素刺激基因（ISGs）的转录，从而增强宿主抗病毒免疫反应。因此，Neurl3 小鼠产生的 I 型 IFN 较少，对病毒感染的易感性增加。总之，我们的研究结果确定了 NEURL3 是 IRF7 的 E3 泛素连接酶，并为宿主抗病毒免疫信号中 IRF7 的正调控提供了新的视角。
