Article | Published:

The methyltransferase PRMT6 attenuates antiviral innate immunity by blocking TBK1–IRF3 signaling

Cellular & Molecular Immunology (2018) | Download Citation



Protein arginine methyltransferases (PRMTs) play diverse biological roles and are specifically involved in immune cell development and inflammation. However, their role in antiviral innate immunity has not been elucidated. Viral infection triggers the TBK1–IRF3 signaling pathway to stimulate the production of type-I interferon, which mediates antiviral immunity. We performed a functional screen of the nine mammalian PRMTs for regulators of IFN-β expression and found that PRMT6 inhibits the antiviral innate immune response. Viral infection also upregulated PRMT6 protein levels. We generated PRMT6-deficient mice and found that they exhibited enhanced antiviral innate immunity. PRMT6 deficiency promoted the TBK1–IRF3 interaction and subsequently enhanced IRF3 activation and type-I interferon production. Mechanistically, viral infection enhanced the binding of PRMT6 to IRF3 and inhibited the interaction between IRF3 and TBK1; this mechanism was independent of PRMT6 methyltransferase activity. Thus, PRMT6 inhibits antiviral innate immunity by sequestering IRF3, thereby blocking TBK1-IRF3 signaling. Our work demonstrates a methyltransferase-independent role for PRMTs. It also identifies a negative regulator of the antiviral immune response, which may protect the host from the damaging effects of an overactive immune system and/or be exploited by viruses to escape immune detection.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from $8.99

All prices are NET prices.

Additional information

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

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

  2. 2.

    Cao, X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol. 16, 35–50 (2016).

  3. 3.

    Gurtler, C. & Bowie, A. G. Innate immune detection of microbial nucleic acids. Trends Microbiol. 21, 413–420 (2013).

  4. 4.

    Goubau, D., Deddouche, S. & Reis e Sousa, C. Cytosolic sensing of viruses. Immunity 38, 855–869 (2013).

  5. 5.

    Paludan, S. R. & Bowie, A. G. Immune sensing of DNA. Immunity 38, 870–880 (2013).

  6. 6.

    Ablasser, A. et al. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat. Immunol. 10, 1065–1072 (2009).

  7. 7.

    Kato, H. et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J. Exp. Med. 205, 1601–1610 (2008).

  8. 8.

    Loo, Y. M. & Gale, M. Jr. Immune signaling by RIG-I-like receptors. Immunity 34, 680–692 (2011).

  9. 9.

    Goubau, D. et al. Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5’-diphosphates. Nature 514, 372–375 (2014).

  10. 10.

    Cai, X., Chiu, Y. H. & Chen, Z. J. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol. Cell 54, 289–296 (2014).

  11. 11.

    Unterholzner, L. et al. IFI16 is an innate immune sensor for intracellular DNA. Nat. Immunol. 11, 997–1004 (2010).

  12. 12.

    Zhang, Z. et al. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat. Immunol. 12, 959–965 (2011).

  13. 13.

    Chen, K., Liu, J. & Cao, X. Regulation of type I interferon signaling in immunity and inflammation: a comprehensive review. J. Autoimmun. 83, 1–11 (2017).

  14. 14.

    Liu, J., Qian, C. & Cao, X. Post-translational modification control of innate immunity. Immunity 45, 15–30 (2016).

  15. 15.

    Li X., et al. The tyrosine kinase Src promotes phosphorylation of the kinase TBK1 to facilitate type I interferon production after viral infection. Sci Signal 10, eaae0435 (2017).

  16. 16.

    Gabhann, J. N. et al. Absence of SHIP-1 results in constitutive phosphorylation of tank-binding kinase 1 and enhanced TLR3-dependent IFN-beta production. J. Immunol. 184, 2314–2320 (2010).

  17. 17.

    Zhao, Y. et al. PPM1B negatively regulates antiviral response via dephosphorylating TBK1. Cell. Signal. 24, 2197–2204 (2012).

  18. 18.

    McCoy, C. E., Carpenter, S., Palsson-McDermott, E. M., Gearing, L. J. & O’Neill, L. A. Glucocorticoids inhibit IRF3 phosphorylation in response to Toll-like receptor-3 and -4 by targeting TBK1 activation. J. Biol. Chem. 283, 14277–14285 (2008).

  19. 19.

    Wang, C. et al. The E3 ubiquitin ligase Nrdp1 ‘preferentially’ promotes TLR-mediated production of type I interferon. Nat. Immunol. 10, 744–752 (2009).

  20. 20.

    Cui, J. et al. NLRP4 negatively regulates type I interferon signaling by targeting the kinase TBK1 for degradation via the ubiquitin ligase DTX4. Nat. Immunol. 13, 387–395 (2012).

  21. 21.

    Zhang, M. et al. TRAF-interacting protein (TRIP) negatively regulates IFN-beta production and antiviral response by promoting proteasomal degradation of TANK-binding kinase 1. J. Exp. Med. 209, 1703–1711 (2012).

  22. 22.

    Li, X. et al. Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat. Immunol. 17, 806–815 (2016).

  23. 23.

    Saitoh, T. et al. Negative regulation of interferon-regulatory factor 3-dependent innate antiviral response by the prolyl isomerase Pin1. Nat. Immunol. 7, 598–605 (2006).

  24. 24.

    Li, S. et al. The tumor suppressor PTEN has a critical role in antiviral innate immunity. Nat. Immunol. 17, 241–249 (2015).

  25. 25.

    Blanc, R. S. & Richard, S. Arginine methylation: the coming of age. Mol. Cell 65, 8–24 (2017).

  26. 26.

    Biggar, K. K. & Li, S. S. Non-histone protein methylation as a regulator of cellular signalling and function. Nat. Rev. Mol. Cell Biol. 16, 5–17 (2015).

  27. 27.

    Wei, H., Mundade, R., Lange, K. C. & Lu, T. Protein arginine methylation of non-histone proteins and its role in diseases. Cell Cycle 13, 32–41 (2014).

  28. 28.

    Yang, Y. & Bedford, M. T. Protein arginine methyltransferases and cancer. Nat. Rev. Cancer 13, 37–50 (2012).

  29. 29.

    Greenblatt, S. M., Liu, F. & Nimer, S. D. Arginine methyltransferases in normal and malignant hematopoiesis. Exp. Hematol. 44, 435–441 (2016).

  30. 30.

    Liu, F. et al. Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis. J. Clin. Invest. 125, 3532–3544 (2015).

  31. 31.

    Kim, J. H. et al. The role of protein arginine methyltransferases in inflammatory responses. Mediat. Inflamm. 2016, 4028353 (2016).

  32. 32.

    Infantino, S. et al. Arginine methylation of the B cell antigen receptor promotes differentiation. J. Exp. Med. 207, 711–719 (2010).

  33. 33.

    Ying, Z. et al. Histone arginine methylation by PRMT7 controls germinal center formation via regulating Bcl6 transcription. J. Immunol. 195, 1538–1547 (2015).

  34. 34.

    Guccione, E. et al. Methylation of histone H3R2 by PRMT6 and H3K4 by an MLL complex are mutually exclusive. Nature 449, 933–937 (2007).

  35. 35.

    Hyllus, D. et al. PRMT6-mediated methylation of R2 in histone H3 antagonizes H3 K4 trimethylation. Genes Dev. 21, 3369–3380 (2007).

  36. 36.

    Waldmann, T. et al. Methylation of H2AR29 is a novel repressive PRMT6 target. Epigenetics Chromatin 4, 11 (2011).

  37. 37.

    Poulard, C., Corbo, L., & Le Romancer, M. Protein arginine methylation/demethylation and cancer. Oncotarget 7, 67532–67550 (2016).

  38. 38.

    Di Lorenzo, A., Yang, Y., Macaluso, M. & Bedford, M. T. A gain-of-function mouse model identifies PRMT6 as a NF-kappaB coactivator. Nucleic Acids Res. 42, 8297–8309 (2014).

  39. 39.

    Liu, X. et al. Intracellular MHC class II molecules promote TLR-triggered innate immune responses by maintaining activation of the kinase Btk. Nat. Immunol. 12, 416–424 (2011).

  40. 40.

    Han, C. et al. Integrin CD11b negatively regulates TLR-triggered inflammatory responses by activating Syk and promoting degradation of MyD88 and TRIF via Cbl-b. Nat. Immunol. 11, 734–742 (2010).

  41. 41.

    Chen, W. et al. Induction of Siglec-G by RNA viruses inhibits the innate immune response by promoting RIG-I degradation. Cell 152, 467–478 (2013).

  42. 42.

    Neault, M., Mallette, F. A., Vogel, G., Michaud-Levesque, J. & Richard, S. Ablation of PRMT6 reveals a role as a negative transcriptional regulator of the p53 tumor suppressor. Nucleic Acids Res. 40, 9513–9521 (2012).

  43. 43.

    Phalke, S. et al. p53-Independent regulation of p21Waf1/Cip1 expression and senescence by PRMT6. Nucleic Acids Res. 40, 9534–9542 (2012).

  44. 44.

    Nakakido, M. et al. PRMT6 increases cytoplasmic localization of p21CDKN1A in cancer cells through arginine methylation and makes more resistant to cytotoxic agents. Oncotarget 6, 30957–30967 (2015).

  45. 45.

    Chen, L. T., Hu, M. M., Xu, Z. S., Liu, Y. & Shu, H. B. MSX1 modulates RLR-mediated innate antiviral signaling by facilitating assembly of TBK1-associated complexes. J. Immunol. 197, 199–207 (2016).

  46. 46.

    Wang, F. et al. S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3. Nat. Immunol. 17, 514–522 (2016).

  47. 47.

    Gates, L. T. & Shisler, J. L. cFLIPL Interrupts IRF3-CBP-DNA Interactions To Inhibit IRF3-Driven Transcription. J. Immunol. 197, 923–933 (2016).

  48. 48.

    Uhlmann, T. et al. A method for large-scale identification of protein arginine methylation. Mol. Cell. Proteomics 11, 1489–1499 (2012).

  49. 49.

    Guo, A. et al. Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol. Cell. Proteomics 13, 372–387 (2014).

Download references


This work was supported by grants from the National Key R&D program of China (2018YFA0507401), National Natural Science Foundation of China (31390431, 31522019, 81471568, 80178104, and 31770945), and the CAMS Innovation Fund for Medical Sciences (2016-12M-1-003). We thank Ms. Xiaofei Li for technical assistance and Life Science Editors for editing assistance.

Author information

Author notes

  1. These authors contributed equally: Hua Zhang, Chaofeng Han.


  1. National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, 200433, China

    • Hua Zhang
    • , Chaofeng Han
    • , Tianliang Li
    • , Nan Li
    •  & Xuetao Cao
  2. Department of Immunology & Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China

    • Xuetao Cao


  1. Search for Hua Zhang in:

  2. Search for Chaofeng Han in:

  3. Search for Tianliang Li in:

  4. Search for Nan Li in:

  5. Search for Xuetao Cao in:


X.C. designed and supervised the study. H.Z., C.H., T.L., and N.L. performed the experiments. H.Z., C.H., and X.C. analyzed the data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Xuetao Cao.

Electronic supplementary material

About this article

Publication history