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

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.

Simultaneous CRISPR screening and spatial transcriptomics reveals intracellular, intercellular, and functional transcriptional circuits

“…Notably, significant effects from these perturbations are highly concordant between Perturb-FISH datasets, and they agree with the current understanding of the pathway as the knock-out of the main LPS receptor TLR4 is expected to downregulate genes from the immune response like TNF or IL1a 23,24 . Similarly, CD14 KO 25 and IRF3 KO 26 were both shown to upregulate TNF expression in response to LPS.…”

A conserved methyltransferase active site residue of Zika virus NS5 is required for the restriction of STING activation and interferon expression

“…IRF3 is a critical transcription activator in IFN induction that plays an important role in the innate immune system. The phosphorylation and translocation of IRF3 are critical for the activation of type I IFN production [26][27][28]. Here, we evaluated the role of NS5 in the regulation of HSV-1-induced IRF3 phosphorylation and nuclear translocation.…”

How Different Pathologies Are Affected by IFIT Expression

“…Along with IRF-3/7, IκB also becomes phosphorylated, thereby activating nuclear factor-κB (NF-κB) [ 6 , 14 ]. After dissociating from IκB, NF-κB is translocated to the nucleus and upregulates the expression of proinflammatory cytokines, such as tumor necrosis factor α (TNFα), interleukin-2 (IL-2), IL-6, IL-8, and IL-12 [ 14 , 15 ].…”