A FOXO3–IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses

Abstract

Antiviral responses must be tightly regulated to rapidly defend against infection while minimizing inflammatory damage. Type 1 interferons (IFN-I) are crucial mediators of antiviral responses1 and their transcription is regulated by a variety of transcription factors2; principal amongst these is the family of interferon regulatory factors (IRFs)3. The IRF gene regulatory networks are complex and contain multiple feedback loops. The tools of systems biology are well suited to elucidate the complex interactions that give rise to precise coordination of the interferon response. Here we have used an unbiased systems approach to predict that a member of the forkhead family of transcription factors, FOXO3, is a negative regulator of a subset of antiviral genes. This prediction was validated using macrophages isolated from Foxo3-null mice. Genome-wide location analysis combined with gene deletion studies identified the Irf7 gene as a critical target of FOXO3. FOXO3 was identified as a negative regulator of Irf7 transcription and we have further demonstrated that FOXO3, IRF7 and IFN-I form a coherent feed-forward regulatory circuit. Our data suggest that the FOXO3-IRF7 regulatory circuit represents a novel mechanism for establishing the requisite set points in the interferon pathway that balances the beneficial effects and deleterious sequelae of the antiviral response.

Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7

“…Moreover, FOXO3 negatively regulates NF-kB activation (23), and FOXO3 is controlled by IKK-ε for regulating IFN-b expression (25). Intriguingly, FOXO3 has also been identified as a negative regulator of IRF7 transcription to participate in the antiviral response (26). Therefore, the function of FOXO3 in negatively regulating innate immunity response is well recognized.…”

“…On the one hand, FOXO3 functions as a suppressor of NF-kB activation (23); on the other hand, IKK-a and IKK-b, two important kinases involved in NF-kB activation, phosphorylate and inactivate FOXO3 upon TNF-a stimulation (24). Recently, FOXO3 was reported to regulate IFN-b expression in an IKK-ε-controlled manner (25); additionally, the FOXO3-IRF7 gene regulatory circuit was also found to be crucial in antiviral response (26). However, the physiological role and the underlying mechanisms of FOXO3 in immunity are still poorly understood.…”

ATF3 Is a Key Regulator of Macrophage IFN Responses

“…2/2 BMDMs, spontaneous basal ISG expression is also observed in macrophages deficient in other important IFN regulators, including TREX1, SAMHD1, and the transcriptional repressor FOXO3 (52)(53)(54)(55). Considering the potential detrimental effects of excessive IFN-b to the host, its production is tightly controlled, including on the transcriptional level.…”

Data integration for identification of important transcription factors of STAT6-mediated cell fate decisions

“…Recently, Subramanian et al (2015) summarized the potential of data integration and network analysis for uncovering physiological processes of immune cells. For instance, in macrophages, gene expression dynamics and scanning for TF-binding sequence motifs have been used to elucidate transcriptional networks on a large scale (Ramsey et al, 2008;Litvak et al, 2012), while a combination of genome-wide mRNA expression data and network perturbation using methods such as RNAi knockdown was applied to identify useful intervention strategies in infections (König et al, 2010). In T helper (Th) cells, Ciofani et al (2012) demonstrated the power of data integration to construct a regulatory network for Th17 cell differentiation: they applied an integrative approach to delineate the Th17 cell global transcriptional regulatory network using meta-analysis of genome occupancy of multiple TFs, RNA-seq data of TF-deficient T cells, and immune cell transcriptome data.…”