2. Academic Validation
  3. VRK2 is involved in the innate antiviral response by promoting mitostress-induced mtDNA release

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

  • Cell Mol Immunol. 2021 May;18(5):1186-1196. doi: 10.1038/s41423-021-00673-0.
Wen-Rui He 1 2,  Li-Bo Cao 1 2,  Yu-Lin Yang 1 2,  Duo Hua 1 2,  Ming-Ming Hu 3 4,  Hong-Bing Shu 5 6
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
  • 2 Research Unit of Innate Immune and Inflammatory Diseases, Chinese Academy of Medical Sciences, Wuhan, China.
  • 3 Department of Infectious Diseases, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. mmhu@whu.edu.cn.
  • 4 Research Unit of Innate Immune and Inflammatory Diseases, Chinese Academy of Medical Sciences, Wuhan, China. mmhu@whu.edu.cn.
  • 5 Department of Infectious Diseases, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China. shuh@whu.edu.cn.
  • 6 Research Unit of Innate Immune and Inflammatory Diseases, Chinese Academy of Medical Sciences, Wuhan, China. shuh@whu.edu.cn.
PMID: 33785841 DOI: 10.1038/s41423-021-00673-0
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.

Keywords

Mita/Sting; cGAS; innate immune response; mitochondrial DNA; mitostress.

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