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VRK2 is involved in the innate antiviral response by promoting mitostress-induced mtDNA release

Abstract

Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The regulation of mtDNA release upon mitostress remains uncharacterized. Here, we identified mitochondria-associated vaccinia virus-related kinase 2 (VRK2) as a key regulator of this process. VRK2 deficiency inhibited the induction of antiviral genes and caused earlier and higher mortality in mice after viral infection. Upon viral infection, VRK2 associated with voltage-dependent anion channel 1 (VDAC1) and promoted VDAC1 oligomerization and mtDNA release, leading to the cGAS-mediated innate immune response. VRK2 was also required for mtDNA release and cGAS-mediated innate immunity triggered by nonviral factors that cause Ca2+ overload but was not required for the cytosolic nucleic acid-triggered innate immune response. Thus, VRK2 plays a crucial role in the mtDNA-triggered innate immune response and may be a potential therapeutic target for infectious and autoimmune diseases associated with mtDNA release.

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Acknowledgements

This work was supported by grants from the State Key R&D Program of China (2017YFA0505800), the National Natural Science Foundation of China (31830024, 31922021, 31771555, 31630045, and 31801188), and the CAMS Innovation Fund for Medical Sciences (2019-I2M-5-071).

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W.R.H., M.M.H., and H.B.S. conceived and designed the study. W.R.H., L.B.C., Y.L.Y., and D.H. performed the experiments. All authors analyzed the data. W.R.H., M.M.H., and H.B.S. wrote the manuscript.

Corresponding authors

Correspondence to Ming-Ming Hu or Hong-Bing Shu.

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The authors declare no competing interests.

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He, WR., Cao, LB., Yang, YL. et al. VRK2 is involved in the innate antiviral response by promoting mitostress-induced mtDNA release. Cell Mol Immunol 18, 1186–1196 (2021). https://doi.org/10.1038/s41423-021-00673-0

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Keywords

  • cGAS
  • Mita/Sting
  • mitostress
  • innate immune response
  • mitochondrial DNA

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