DDX6 is involved in the pathogenesis of inflammatory diseases via NF-κB activation

• Published in: Biochemical and biophysical research communications 2024-04, Vol.703, p.149666, Article 149666
• Main Authors: Naito, Seiichiro, Tanaka, Hiroki, Jiang, Jing-Jing, Tarumi, Masato, Hashimoto, Ari, Tanaka, Yuki, Murakami, Kaoru, Kubota, Shimpei I., Hojyo, Shintaro, Hashimoto, Shigeru, Murakami, Masaaki
• Format: Article
• Language: English
• Subjects: chemokines; DDX6; DEAD-box RNA helicases; dermatitis; Gene Expression Regulation; genes; IL-6; Inflammation; interleukin-6; Interleukin-6 - metabolism; metabolism; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha - metabolism; NF-κB; pathogenesis; phosphorylation; RNA; Signal Transduction; therapeutics; Transcription Factor RelA - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.149666

The IL-6 amplifier was originally discovered as a mechanism for the enhanced activation of NF-κB in non-immune cells. In the IL-6 amplifier, IL-6-STAT3 and NF-κB stimulation is followed by an excessive production of IL-6, chemokines, and growth factors to develop chronic inflammation preceding the development of inflammatory diseases. Previously, using a shRNA-mediated genome-wide screening, we found that DEAD-Box Helicase 6 (DDX6) is a candidate positive regulator of the amplifier. Here, we investigate whether DDX6 is involved in the pathogenesis of inflammatory diseases via the IL-6 amplifier. We found that DDX6-silencing in non-immune cells suppressed the NF-κB pathway and inhibited activation of the IL-6 amplifier, while the forced expression of DDX6 enhanced NF-κB promoter activity independent of the RNA helicase activity of DDX6. The imiquimod-mediated dermatitis model was suppressed by the siRNA-mediated gene downregulation of DDX6. Furthermore, silencing DDX6 significantly reduced the TNF-α-induced phosphorylation of p65/RelA and IκBα, nuclear localization of p65, and the protein levels of IκBα. Mechanistically, DDX6 is strongly associated with p65 and IκBα, but not TRADD, RIP, or TRAF2, suggesting a novel function of DDX6 as an adaptor protein in the NF-κB pathway. Thus, our findings demonstrate a possible role of DDX6 beyond RNA metabolism and suggest DDX6 is a therapeutic target for inflammatory diseases. •DDX6- in non-immune cells augments NF-κB activation via enhancing phosphorylation of p65/RelA and IκBα, and nuclear localization of p65.•The downregulation of DDX6 suppresses a NF-κB-mediated skin inflammatory disease model.•DDX6 promotes the NF-κB transcription activation, independent of its RNA helicase activity.•DDX6 binds to some TNFR- NF-κB signaling molecules, including IκBα, SKP1, and p65.•DDX6 might be a therapeutic target for inflammatory diseases.