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

Abstract

Forkhead box O (FOXO)3, a member of the FOXO family of transcription factors, plays key roles in various cellular processes, including development, longevity, reproduction, and metabolism. Recently, FOXO3 has also been shown to be involved in modulating the immune response. However, how FOXO3 regulates immunity and the underlying mechanisms are still largely unknown. In this study, we show that zebrafish (Danio rerio) foxo3b, an ortholog of mammalian FOXO3, is induced by polyinosinic-polycytidylic acid stimulation and spring viremia of carp virus (SVCV) infection. We found that foxo3b interacted with irf3 and irf7 to inhibit ifr3/irf7 transcriptional activity, thus resulting in suppression of SVCV or polyinosinic-polycytidylic acid–induced IFN activation. By suppressing expression of key antiviral genes, foxo3b negatively regulated the cellular antiviral response. Furthermore, upon SVCV infection, the expression of the key antiviral genes was significantly enhanced in foxo3b-null zebrafish larvae compared with wild-type larvae. Additionally, the replication of SVCV was inhibited in foxo3b-null zebrafish larvae, leading to a higher survival rate. Our findings suggest that by suppressing irf3/irf7 activity, zebrafish foxo3b negatively regulates the antiviral response, implicating the vital role of the FOXO gene family in innate immunity.

Zebrafish prmt7 negatively regulates antiviral responses by suppressing the retinoic acid‐inducible gene‐I‐like receptor signaling

“…34 The expression levels of ifn1, mxc, lta, and pkz were higher in prmt7-null larvae compared with those in the WT larvae after SVCV infection ( Figure 6C-F). 34 The expression levels of ifn1, mxc, lta, and pkz were higher in prmt7-null larvae compared with those in the WT larvae after SVCV infection ( Figure 6C-F).…”

“…34 In EPC cells, both poly(I:C) treatment and SVCV infection could effectively activate these four promoters' activity (Supporting Figures S2A,B). Initially, we performed reporter assays.…”

“…34 Ci-IFN1-luc was a gift from Dr Jianguo Su 35 (Huazhong Agricultural University, Wuhan, China). in the pGL3-Basic vector (Promega, Madison, WI, USA), and the ISRE luciferase reporter construct (ISRE-luc) containing five ISRE motifs were described previously.…”

“…34 If the HMA results were positive, the remaining embryos were raised up to adulthood as the F0 generation, and then back-crossed with WT zebrafish (strain AB) to generate the F1 generation, which were genotyped by HMA initially and confirmed by sequencing of target sites. Cas9 RNA (0.75-1.25 ng/per embryo) and sgRNA (0.075 ng/per embryo) were mixed and injected into embryos at the one-cell stage.…”

“…34 To determine whether zebrafish prmt7 inhibits IFN expression through its effect on the RLR signaling, we examined the activity of ISRE-Luc. 34 To determine whether zebrafish prmt7 inhibits IFN expression through its effect on the RLR signaling, we examined the activity of ISRE-Luc.…”