College of Life Sciences, Henan Agricultural University, Zhengzhou 450002, China.
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
Int Immunopharmacol. 2021 Jan;90:107152. doi: 10.1016/j.intimp.2020.107152. Epub 2020 Nov 10.
RNA virus infection activates the RIG-I-like Receptor (RLR) signaling pathway to produce type I interferons (IFNs), the key components of the antiviral immune response. Forkhead box O1 (FoxO1) is a host transcription factor that participates in multiple biological processes. In this study, FoxO1 was identified as a critical negative regulator of RIG-I-triggered signaling. FoxO1 promoted Sendai virus (SeV) replication and downregulated type I IFN production. Upon SeV infection, FoxO1 suppressed K63-linked ubiquitination of TRAF3 and the interaction between TRAF3 and TBK1, after which the production of type I IFNs via the interferon regulatory transcription factor 3 (IRF3) pathways was reduced. In addition, FoxO1 destabilized IRF3 by facilitating E3 ligase TRIM22- or TRIM21-mediated K48-linked ubiquitination of IRF3. Moreover, the inhibitory effect of FoxO1 was found to depend on its DNA binding domain (DBD). Thus, our findings highlight novel important roles of FoxO1 in controlling RLR-mediated antiviral innate immunity.
RNA 病毒感染激活 RIG-I 样受体（RLR）信号通路，产生 I 型干扰素（IFNs），这是抗病毒免疫反应的关键组成部分。叉头框 O1（FoxO1）是一种参与多种生物学过程的宿主转录因子。在这项研究中，FoxO1 被确定为 RIG-I 触发信号的关键负调控因子。FoxO1 促进了仙台病毒（SeV）的复制，并下调了 I 型 IFN 的产生。在 SeV 感染后，FoxO1 抑制了 TRAF3 的 K63 连接泛素化和 TRAF3 与 TBK1 的相互作用，从而降低了干扰素调节转录因子 3（IRF3）途径产生的 I 型 IFNs。此外，FoxO1 通过促进 E3 连接酶 TRIM22 或 TRIM21 介导的 IRF3 的 K48 连接泛素化，使 IRF3 不稳定。此外，发现 FoxO1 的抑制作用依赖于其 DNA 结合域（DBD）。因此，我们的研究结果强调了 FoxO1 在控制 RLR 介导的抗病毒先天免疫中的新的重要作用。
