Abstract:
Interferon (IFN) regulatory factors (IRF) are key transcription factors in cellular antiviral responses. IRF7, a virus-inducible IRF, expressed primarily in myeloid cells, is required for transcriptional induction of interferon α and antiviral genes. IRF7 is activated by virus-induced phosphorylation in the cytoplasm, leading to its translocation to the nucleus for transcriptional activity. Here, we revealed a nontranscriptional activity of IRF7 contributing to its antiviral functions. IRF7 interacted with the pro-inflammatory transcription factor NF-κB-p65 and inhibited the induction of inflammatory target genes. Using knockdown, knockout, and overexpression strategies, we demonstrated that IRF7 inhibited NF-κB-dependent inflammatory target genes, induced by virus infection or toll-like receptor stimulation. A mutant IRF7, defective in transcriptional activity, interacted with NF-κB-p65 and suppressed NF-κB-induced gene expression. A single-action IRF7 mutant, active in anti-inflammatory function, but defective in transcriptional activity, efficiently suppressed Sendai virus and murine hepatitis virus replication. We, therefore, uncovered an anti-inflammatory function for IRF7, independent of transcriptional activity, contributing to the antiviral response of IRF7.
摘要:
干扰素(IFN)调节因子(IRF)是细胞抗病毒反应中的关键转录因子。IRF7,一种病毒诱导的IRF,主要在骨髓细胞中表达,是IFNα和抗病毒基因的转录诱导所必需的。IRF7被病毒诱导的细胞质磷酸化激活,导致其易位到细胞核进行转录活性。这里,我们发现IRF7的非转录活性有助于其抗病毒功能。IRF7与促炎转录因子NF-κB-p65相互作用并抑制炎症靶基因的诱导。使用击倒,击倒,和过度表达策略,我们证明IRF7抑制NF-κB依赖性炎症靶基因,由病毒感染或Toll样受体(TLR)刺激诱导。突变IRF7,转录活性缺陷,与NF-κB-p65相互作用并抑制NF-κB诱导的基因表达。单动IRF7突变体,抗炎功能活跃,但是转录活性有缺陷,有效抑制仙台病毒和鼠肝炎病毒的复制。我们,因此,揭示了IRF7的抗炎功能,与转录活性无关,有助于IRF7的抗病毒反应。