Noncanonical IRF3 function mediates STING-dependent pro-inflammatory cytokine production in macrophages
STING is an important component in the host innate immune system where its activation by cyclic dinucleotides culminates in the production of interferons and pro-inflammatory cytokines that mediate host defence against infection. While the mechanisms that govern STING-induced interferon production have been comprehensively characterised, how pro-inflammatory cytokines are produced downstream of STING remains less understood. Here we discover that IRF3 is critical for effective STING-mediated inflammatory cytokine production from macrophages as those lacking IRF3 display significant defects. Interestingly, the loss of IRF3 does not impact the activation of the prominent pro-inflammatory transcription factor, NF-κB, but rather affects the AP-1 transcriptional complex. We further discover the role of IRF3 in STING inflammatory responses is independent of its phosphorylation and distinct from its role as a transcription factor for induction of type I interferons. This additional activity of IRF3 is dependent on its recruitment to the previously defined IRF3 binding motif within the C-terminal tail of STING. Hence, our findings reveal an unexpected noncanonical function of IRF3 that is critical for mediating STING-induced pro-inflammatory cytokines from macrophages.
Authors
- Mireille H. Lahoud (ORCID: https://orcid.org/0000-0001-8472-6201)
- Paul J. Hertzog (ORCID: https://orcid.org/0000-0002-1373-8472)
- Linda M. Wakim (ORCID: https://orcid.org/0000-0003-1752-9579)
- Nicole A. de Weerd (ORCID: https://orcid.org/0000-0002-7985-189X)
- Peter J. Crack (ORCID: https://orcid.org/0000-0002-5030-0330)
- Katherine R. Balka (ORCID: https://orcid.org/0000-0003-0643-3360)
- Kim L. Good‐Jacobson (ORCID: https://orcid.org/0000-0003-1891-7274)
- Rajan Venkatraman (ORCID: https://orcid.org/0009-0002-0244-0520)
- Zoe Magill (ORCID: https://orcid.org/0000-0003-2743-0804)
- Meredith O’Keeffe
- Olivia R Lamb
- Kate McArthur (ORCID: https://orcid.org/0000-0002-8838-4146)
- Dominic De Nardo (ORCID: https://orcid.org/0000-0002-7045-4695)
- Le T Hoang (ORCID: https://orcid.org/0009-0005-9350-6880)
- Ryker Dumbrill (ORCID: https://orcid.org/0009-0003-4399-4279)
Institutions
- University of Bonn (DE)
- The University of Melbourne (AU)
- Discovery Institute (US)
- Hudson Institute of Medical Research (AU)
- Peter Doherty Institute (AU)
- Monash University (AU)
Publication Details
- Journal
- EMBO Reports
- Published
- 2026-05-08
- DOI
- https://doi.org/10.1038/s44319-026-00793-6
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Molecular Biology Organization
- Australian Government
- La Trobe University
- Monash University
- Australian and New Zealand Society for Immunology
- Medical Research Council
- Australian Research Council
- National Health and Medical Research Council
- Faculty of Medicine, Nursing and Health Sciences, Monash University
- Institute for Molecular Bioscience, University Of Queensland