DDX6 is involved in the pathogenesis of inflammatory diseases via NF-κB activation
Copyright © 2024 Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:703 |
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| Enthalten in: |
Biochemical and biophysical research communications - 703(2024) vom: 09. März, Seite 149666 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Naito, Seiichiro [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.03.2024 Date Revised 15.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bbrc.2024.149666 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a DDX6 | |
| 650 | 4 | |a IL-6 | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a NF-κB | |
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| 650 | 7 | |a Transcription Factor RelA |2 NLM | |
| 650 | 7 | |a Tumor Necrosis Factor-alpha |2 NLM | |
| 650 | 7 | |a DDX6 protein, human |2 NLM | |
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| 650 | 7 | |a DEAD-box RNA Helicases |2 NLM | |
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| 700 | 1 | |a Tanaka, Hiroki |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Jing-Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Tarumi, Masato |e verfasserin |4 aut | |
| 700 | 1 | |a Hashimoto, Ari |e verfasserin |4 aut | |
| 700 | 1 | |a Tanaka, Yuki |e verfasserin |4 aut | |
| 700 | 1 | |a Murakami, Kaoru |e verfasserin |4 aut | |
| 700 | 1 | |a Kubota, Shimpei I |e verfasserin |4 aut | |
| 700 | 1 | |a Hojyo, Shintaro |e verfasserin |4 aut | |
| 700 | 1 | |a Hashimoto, Shigeru |e verfasserin |4 aut | |
| 700 | 1 | |a Murakami, Masaaki |e verfasserin |4 aut | |
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