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

Abstract

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
Volume119
Issue number37
DOIs
StatePublished - Sep 13 2022

Bibliographical note

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

Keywords

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

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'IRF3 inhibits nuclear translocation of NF-κB to prevent viral inflammation'. Together they form a unique fingerprint.

Cite this