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VRK1 promotes DNA-induced type I interferon production

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Abstract

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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Data availability

No datasets were generated or analysed during the current study.

Abbreviations

PRRs:

Pattern recognition receptors

PAMPs:

Pathogen-associated molecular patterns

VRKs:

Vaccinia-Related Kinases

BMDMs:

Bone marrow-derived macrophages

cGAS:

Cytosolic GAMP synthase

TBK1:

TANK-binding kinase 1

RIG-I:

RNA helicases retinoic acid-inducible gene I

MDA5:

Melanoma differentiation-associated gene 5

DAI:

DNA-dependent activator of IFN-regulatory factors

AIM2:

Absent in melanoma 2

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Funding

This work was supported by the Natural Science Foundation of Jiangsu Province (BK20221029).

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Author notes

  1. Zhechen Fan and Xiong Wang contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China

    Zhechen Fan & Hao Cheng

  2. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China

    Xiong Wang & Mingyu Pan

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  1. Zhechen Fan
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  3. Hao Cheng
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Contributions

M.P. and H.C. wrote the main manuscript text and Z.F. and X.W. prepared Figs. 1, 2, 3, 4, 5 and 6. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Hao Cheng or Mingyu Pan.

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Ethical approval

All animal experiments were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, with approval of the Institutional Ethics Committee of China Pharmaceutical University (Approval Number 2022–04–002).

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The authors declare no competing interests.

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Fan, Z., Wang, X., Cheng, H. et al. VRK1 promotes DNA-induced type I interferon production. Mol Biol Rep 51, 453 (2024). https://doi.org/10.1007/s11033-024-09414-8

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