Fan Shumin, Popli Sonam, Chakravarty Sukanya, Chakravarti Ritu, Chattopadhyay Saurabh
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Science, Toledo, Ohio, USA.
Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Science, Toledo, Ohio, USA; Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
J Biol Chem. 2024 Apr;300(4):107200. doi: 10.1016/j.jbc.2024.107200. Epub 2024 Mar 18.
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.
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是一种病毒诱导型IRF，主要在髓系细胞中表达，是干扰素α和抗病毒基因转录诱导所必需的。IRF7在细胞质中通过病毒诱导的磷酸化被激活，导致其转位至细胞核发挥转录活性。在此，我们揭示了IRF7有助于其抗病毒功能的一种非转录活性。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。使用敲低、敲除和过表达策略，我们证明IRF7抑制由病毒感染或Toll样受体刺激诱导的NF-κB依赖性炎症靶基因。一种转录活性有缺陷的IRF7突变体与NF-κB-p65相互作用，并抑制NF-κB诱导的基因表达。一种具有抗炎功能但转录活性有缺陷的单功能IRF7突变体有效抑制了仙台病毒和鼠肝炎病毒的复制。因此，我们发现了IRF7的一种抗炎功能，其独立于转录活性，有助于IRF7的抗病毒反应。
