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Type I interferon (IFN) responses are central to antiviral immunity and are classically viewed as
transcriptional programs driven by IFN regulatory factors (IRFs). Our work reveals novel,
transcription-independent functions of the interferon system that expand its antiviral and
immunoregulatory capacity. We identified a non-transcriptional activity of IRF3 that promotes
apoptosis of virus-infected cells, providing an alternative mechanism to limit viral replication.
More recently, we uncovered an additional function of IRF3: suppression of NF-κB–dependent
inflammatory gene expression through direct interactions with NF-κB components. This
pathway, termed RIKA (Repression of IRF3-induced NF-κB Activation), is essential for limiting
macrophage-driven inflammation and protecting against respiratory viral infection in vivo. We
further demonstrate that IRF7, which contains a conserved NF-κB-binding motif, shares this
anti-inflammatory activity, revealing a broader regulatory module within the interferon system.
Ongoing studies show that viruses selectively antagonize these non-canonical IRF functions,
underscoring their physiological relevance during host–virus conflict. |