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.
| Original language | English |
|---|---|
| Article number | 107200 |
| Journal | Journal of Biological Chemistry |
| Volume | 300 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2024 |
Bibliographical note
Publisher Copyright:© 2024 The Authors
Funding
We thank Travis Taylor, Kevin Pan, and Randall Worth for critical input on the study and Durga Sharma for technical support. The following reagents were obtained through BEI Resources, National Institute of Allergy and Infectious Diseases, NIH: anti-Murine Coronavirus Nucleocapsid (N) protein (NR-45106), mouse lung epithelium (Let1) cell line (NR-42941), mouse macrophage WT cell line (NR-9456), mouse macrophage Irf7−/− cell line (NR-15636), recombinant murine coronavirus strain icA59 (NR-43000). S. F. S. P. R. C. and Sa. C. conceptualization; S. F. S. P. Su. C. R. C. and Sa. C. data curation; S. F. S. P. Su. C. R. C. and Sa. C. formal analysis; Sa. C. funding acquisition; S. F. S. P. Su. C. and Sa. C. investigation; S. F. S. P. R. C. and Sa. C. methodology; Sa. C. project administration; S. F. R. C. and Sa. C. writing–original draft; S. F. R. C. and Sa. C. writing–review and editing. This work was supported in part by the National Institutes of Health grants AI155545 (Sa. C.), AI165521 (Sa. C.), AA027456 (Sa. C.), and Medical Research Society (Sa. C.), and the University of Toledo College of Medicine and Life Sciences startup funds (Sa. C. and R. C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was supported in part by the National Institutes of Health grants AI155545 (S. Chattopadhyay), AI165521 (S. Chattopadhyay), AA027456 (S. Chattopadhyay), and Medical Research Society (S. Chattopadhyay), and the University of Toledo College of Medicine and Life Sciences startup funds (S. Chattopadhyay and RC). We thank Travis Taylor, Kevin Pan, and Randall Worth for critical input on the study, and Durga Sharma for technical support. The following reagents were obtained through BEI Resources, National Institute of Allergy and Infectious Diseases, NIH: anti-Murine Coronavirus Nucleocapsid (N) protein (NR-45106), mouse lung epithelium (Let1) cell line (NR-42941), mouse macrophage wild type cell line (NR-9456), mouse macrophage Irf7-/- cell line (NR-15636), Recombinant murine coronavirus strain icA59 (NR-43000).
| Funders | Funder number |
|---|---|
| National Institute of Allergy and Infectious F32-AI286447 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI168214 Jason W. Rosch Diseases National Institute of Allergy and Infectious P30 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R00-AI166116 Christopher D. Radka Diseases National Institute of Allergy and Infectious T32-AI106700 Cydney N. Johnson Diseases National Institute of Allergy and Infectious R01AI192221 Jason W. Rosch Diseases National Inst... | |
| University of Toledo College of Medicine and Life Sciences | |
| National Society of Medical Research | |
| BEI Resources | |
| National Institutes of Health (NIH) | NR-43000, AA027456, NR-42941, NR-45106, AI155545, NR-15636, NR-9456, AI165521 |
Keywords
- IRF7
- NF-κB
- antiviral
- innate immunity
- viral inflammation
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
