Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614.
Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195.
Proc Natl Acad Sci U S A. 2022 Sep 13;119(37):e2121385119. doi: 10.1073/pnas.2121385119. Epub 2022 Sep 6.
Interferon (IFN) regulatory factor 3 (IRF3) is a transcription factor activated by phosphorylation in the cytoplasm of a virus-infected cell; by translocating to the nucleus, it induces transcription of IFN-β and other antiviral genes. We have previously reported IRF3 can also be activated, as a proapoptotic factor, by its linear polyubiquitination mediated by the RIG-I pathway. Both transcriptional and apoptotic functions of IRF3 contribute to its antiviral effect. Here, we report a nontranscriptional function of IRF3, namely, the repression of IRF3-mediated NF-κB activity (RIKA), which attenuated viral activation of NF-κB and the resultant inflammatory gene induction. In mice, consequently, Sendai virus infection caused enhanced inflammation in the lungs. Mechanistically, RIKA was mediated by the direct binding of IRF3 to the p65 subunit of NF-κB in the cytoplasm, which prevented its nuclear import. A mutant IRF3 defective in both the transcriptional and the apoptotic activities was active in RIKA and inhibited virus replication. Our results demonstrated IRF3 deployed a three-pronged attack on virus replication and the accompanying inflammation.
干扰素 (IFN) 调节因子 3 (IRF3) 是一种在病毒感染细胞的细胞质中通过磷酸化而被激活的转录因子；通过转位到细胞核，它诱导 IFN-β 和其他抗病毒基因的转录。我们之前曾报道过，IRF3 也可以通过 RIG-I 途径介导的线性多泛素化而被激活，作为一种促凋亡因子。IRF3 的转录和凋亡功能都有助于其抗病毒作用。在这里，我们报告了 IRF3 的一种非转录功能，即抑制 IRF3 介导的 NF-κB 活性（RIKA），这减弱了病毒对 NF-κB 的激活和由此产生的炎症基因诱导。在 小鼠中，因此，仙台病毒感染导致肺部炎症加重。在机制上，RIKA 是通过 IRF3 在细胞质中与 NF-κB 的 p65 亚基的直接结合介导的，这阻止了其核内导入。一个在转录和凋亡活性上都有缺陷的突变型 IRF3 在 RIKA 中是活跃的，并抑制病毒复制。我们的结果表明，IRF3 对病毒复制及其伴随的炎症采取了三管齐下的策略。
