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

Cellular & Molecular Immunology volume 18, pages 1186–1196 (2021)Cite this article

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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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References

  1. Hu, M. M. & Shu, H. B. Innate immune response to cytoplasmic DNA: mechanisms and diseases. Annu Rev. Immunol. 38, 79–98 (2020).

    Article  CAS  PubMed  Google Scholar 

  2. Akira, S., Uematsu, S. & Takeuchi, O. Pathogen recognition and innate immunity. Cell 124, 783–801 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Seth, R. B., Sun, L., Ea, C. K. & Chen, Z. J. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell 122, 669–682 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Xu, L. G., Wang, Y. Y., Han, K. J., Li, L. Y., Zhai, Z. & Shu, H. B. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol. Cell 19, 727–740 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Hu, M. M. & Shu, H. B. Cytoplasmic mechanisms of recognition and defense of microbial nucleic acids. Annu Rev. Cell Dev. Biol. 34, 357–379 (2018).

    Article  CAS  PubMed  Google Scholar 

  7. Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z. J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhong, B. et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29, 538–550 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Wu, J. et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826–830 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Dobbs, N., Burnaevskiy, N., Chen, D., Gonugunta, V. K., Alto, N. M. & Yan, N. STING activation by translocation from the ER is associated with infection and autoinflammatory disease. Cell Host Microbe 18, 157–168 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Holm, C. K. et al. Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING. Nat. Immunol. 13, 737–743 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  14. West, A. P. & Shadel, G. S. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat. Rev. Immunol. 17, 363–375 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Weinberg, S. E., Sena, L. A. & Chandel, N. S. Mitochondria in the regulation of innate and adaptive immunity. Immunity 42, 406–417 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gong, T., Liu, L., Jiang, W. & Zhou, R. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat. Rev. Immunol. 20, 95–112 (2020).

    Article  CAS  PubMed  Google Scholar 

  17. Kim, J. et al. VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science 366, 1531–1536 (2019).

    Article  CAS  PubMed  Google Scholar 

  18. Sliter, D. A. et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258–262 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nezu, J., Oku, A., Jones, M. H. & Shimane, M. Identification of two novel human putative serine/threonine kinases, VRK1 and VRK2, with structural similarity to vaccinia virus B1R kinase. Genomics 45, 327–331 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Li, M. & Yue, W. VRK2, a candidate gene for psychiatric and neurological disorders. Mol. Neuropsychiatry 4, 119–133 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Blanco, S., Santos, C. & Lazo, P. A. Vaccinia-related kinase 2 modulates the stress response to hypoxia mediated by TAK1. Mol. Cell Biol. 27, 7273–7283 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Blanco, S., Sanz-Garcia, M., Santos, C. R. & Lazo, P. A. Modulation of interleukin-1 transcriptional response by the interaction between VRK2 and the JIP1 scaffold protein. PLoS One 3, e1660 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Fernandez, I. F., Perez-Rivas, L. G., Blanco, S., Castillo-Dominguez, A. A., Lozano, J. & Lazo, P. A. VRK2 anchors KSR1-MEK1 to endoplasmic reticulum forming a macromolecular complex that compartmentalizes MAPK signaling. Cell Mol. Life Sci. 69, 3881–3893 (2012).

    Article  CAS  PubMed  Google Scholar 

  24. Vazquez-Cedeira, M. & Lazo, P. A. Human VRK2 (vaccinia-related kinase 2) modulates tumor cell invasion by hyperactivation of NFAT1 and expression of cyclooxygenase-2. J. Biol. Chem. 287, 42739–42750 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hu, M. M. et al. Sumoylation promotes the stability of the DNA sensor cGAS and the adaptor STING to regulate the kinetics of response to DNA virus. Immunity 45, 555–569 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Hu, M. M., Liao, C. Y., Yang, Q., Xie, X. Q. & Shu, H. B. Innate immunity to RNA virus is regulated by temporal and reversible sumoylation of RIG-I and MDA5. J. Exp. Med. 214, 973–989 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Luo, W. W. et al. iRhom2 is essential for innate immunity to DNA viruses by mediating trafficking and stability of the adaptor STING. Nat. Immunol. 17, 1057–1066 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Lian, H. et al. The zinc-finger protein ZCCHC3 binds RNA and facilitates viral RNA sensing and activation of the RIG-I-like receptors. Immunity 49, 438–448.e435 (2018).

    Article  CAS  PubMed  Google Scholar 

  29. Li, M. & Shu, H. B. Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response. Protein Cell 11, 584–599 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Barnett, K. C. et al. Phosphoinositide interactions position cGAS at the plasma membrane to ensure efficient distinction between self- and viral DNA. Cell 176, 1432–1446.e1411 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563–1577 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hu, M. M. et al. Virus-induced accumulation of intracellular bile acids activates the TGR5-beta-arrestin-SRC axis to enable innate antiviral immunity. Cell Res. 29, 193–205 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu, Z. S. et al. G3BP1 promotes DNA binding and activation of cGAS. Nat. Immunol. 20, 18–28 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Kumar, C. S., Dey, D., Ghosh, S. & Banerjee, M. Breach: host membrane penetration and entry by nonenveloped viruses. Trends Microbiol. 26, 525–537 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Riley, J. S. & Tait, S. W. Mitochondrial DNA in inflammation and immunity. EMBO Rep. 21, e49799 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Youle, R. J. & van der Bliek, A. M. Mitochondrial fission, fusion, and stress. Science 337, 1062–1065 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. White, M. J. et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159, 1549–1562 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Monsalve, D. M., Merced, T., Fernandez, I. F., Blanco, S., Vazquez-Cedeira, M. & Lazo, P. A. Human VRK2 modulates apoptosis by interaction with Bcl-xL and regulation of BAX gene expression. Cell Death Dis. 4, e513 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Birendra, K. et al. VRK2A is an A-type lamin-dependent nuclear envelope kinase that phosphorylates BAF. Mol. Biol. Cell 28, 2241–2250 (2017).

    Article  CAS  PubMed Central  Google Scholar 

  40. Hirata, N. et al. Functional characterization of lysosomal interaction of Akt with VRK2. Oncogene 37, 5367–5386 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Caielli, S. et al. Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J. Exp. Med. 213, 697–713 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Clapham, D. E. Calcium signaling. Cell 131, 1047–1058 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Degors, I. M. S., Wang, C., Rehman, Z. U. & Zuhorn, I. S. Carriers break barriers in drug delivery: endocytosis and endosomal escape of gene delivery vectors. Acc. Chem. Res. 52, 1750–1760 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Sun, B. et al. Dengue virus activates cGAS through the release of mitochondrial DNA. Sci. Rep. 7, 3594 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Moriyama, M., Koshiba, T. & Ichinohe, T. Influenza A virus M2 protein triggers mitochondrial DNA-mediated antiviral immune responses. Nat. Commun. 10, 4624 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Benmerzoug, S. et al. STING-dependent sensing of self-DNA drives silica-induced lung inflammation. Nat. Commun. 9, 5226 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Li, S. et al. SFTSV infection induces BAK/BAX-dependent mitochondrial DNA release to trigger NLRP3 inflammasome activation. Cell Rep. 30, 4370–4385.e4377 (2020).

    Article  CAS  PubMed  Google Scholar 

  49. Wang, Y. et al. Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to regulate responses to DNA virus infection. Immunity 46, 393–404 (2017).

    Article  CAS  PubMed  Google Scholar 

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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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Authors and 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

    Wen-Rui He, Li-Bo Cao, Yu-Lin Yang, Duo Hua, Ming-Ming Hu & Hong-Bing Shu

  2. Research Unit of Innate Immune and Inflammatory Diseases, Chinese Academy of Medical Sciences, Wuhan, China

    Wen-Rui He, Li-Bo Cao, Yu-Lin Yang, Duo Hua, Ming-Ming Hu & Hong-Bing Shu

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  1. Wen-Rui He
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Contributions

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.

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

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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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