IRF3 inhibits nuclear translocation of NF-κB to prevent viral inflammation

Sonam Popli, Sukanya Chakravarty, Shumin Fan, Anna Glanz, Siddhesh Aras, Laura E. Nagy, Ganes C. Sen, Ritu Chakravarti, Saurabh Chattopadhyay

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 Irf3―/―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.

Original languageEnglish
Article numbere2121385119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 13 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 the Author(s). Published by PNAS.


  • IRF3
  • NF-κB
  • antiviral
  • innate immunity
  • viral inflammation

ASJC Scopus subject areas

  • General


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