VRK1 promotes DNA-induced type I interferon production
Background Type I interferons (IFNs) are an essential class of cytokines with antitumor, antiviral and immunoregulatory effects. However, over-productive the type I IFNs are tightly associated with autoimmune disorders. Thus, the induction of type I interferons is precisely regulated to maintain immune hemostasis. This study aimed to identify a novel regulator of type I interferon signaling. Methods and results Primary BMDMs, isolated from mice, and human cell lines (HEK293 cells, Hela cells) and murine cell line (MEF cells) were cultured to generate in vitro models. After knockdown VRK1, real-time PCR and dual-luciferase reporter assay were performed to determine the expression level of the type I IFNs and ISGs following HTDNA and Poly (dA:dT) stimulation. Additionally, cells were treated with the VRK1 inhibitor, and the impact of VRK1 inhibition was detected. Upon HTDNA and Poly (dA:dT) stimulation, knockdown of VRK1 attenuated the induction of the type I IFNs and ISGs. Consistently, VRK-IN-1, a potent and selective VRK1 inhibitor, significantly suppressed the induction of the type I IFNs and ISGs in human and murine cell lines. Further, VRK-IN-1 inhibited induction of the type I IFNs in mouse primary BMDMs. Intriguingly, VRK1 potentiated the cGAS-STING- IFN-I axis response at STING level. Conclusions Our study reveals a novel function of VRK1 in regulating the production of type I IFNs. VRK-IN-1 might be a potential lead compound for suppressing aberrant type I IFNs in autoimmune disorders..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:51 |
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| Enthalten in: |
Molecular biology reports - 51(2024), 1 vom: 27. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fan, Zhechen [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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© The Author(s), under exclusive licence to Springer Nature B.V. 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| doi: |
10.1007/s11033-024-09414-8 |
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| funding: |
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| 520 | |a Background Type I interferons (IFNs) are an essential class of cytokines with antitumor, antiviral and immunoregulatory effects. However, over-productive the type I IFNs are tightly associated with autoimmune disorders. Thus, the induction of type I interferons is precisely regulated to maintain immune hemostasis. This study aimed to identify a novel regulator of type I interferon signaling. Methods and results Primary BMDMs, isolated from mice, and human cell lines (HEK293 cells, Hela cells) and murine cell line (MEF cells) were cultured to generate in vitro models. After knockdown VRK1, real-time PCR and dual-luciferase reporter assay were performed to determine the expression level of the type I IFNs and ISGs following HTDNA and Poly (dA:dT) stimulation. Additionally, cells were treated with the VRK1 inhibitor, and the impact of VRK1 inhibition was detected. Upon HTDNA and Poly (dA:dT) stimulation, knockdown of VRK1 attenuated the induction of the type I IFNs and ISGs. Consistently, VRK-IN-1, a potent and selective VRK1 inhibitor, significantly suppressed the induction of the type I IFNs and ISGs in human and murine cell lines. Further, VRK-IN-1 inhibited induction of the type I IFNs in mouse primary BMDMs. Intriguingly, VRK1 potentiated the cGAS-STING- IFN-I axis response at STING level. Conclusions Our study reveals a novel function of VRK1 in regulating the production of type I IFNs. VRK-IN-1 might be a potential lead compound for suppressing aberrant type I IFNs in autoimmune disorders. | ||
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