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Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity

Nature Immunology volume 17, pages 806–815 (2016)Cite this article

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An Erratum to this article was published on 19 July 2016

Abstract

The DNA methyltransferase Dnmt3a has high expression in terminally differentiated macrophages; however, its role in innate immunity remains unknown. Here we report that deficiency in Dnmt3a selectively impaired the production of type I interferons triggered by pattern-recognition receptors (PRRs), but not that of the proinflammatory cytokines TNF and IL-6. Dnmt3a-deficient mice exhibited enhanced susceptibility to viral challenge. Dnmt3a did not directly regulate the transcription of genes encoding type I interferons; instead, it increased the production of type I interferons through an epigenetic mechanism by maintaining high expression of the histone deacetylase HDAC9. In turn, HDAC9 directly maintained the deacetylation status of the key PRR signaling molecule TBK1 and enhanced its kinase activity. Our data add mechanistic insight into the crosstalk between epigenetic modifications and post-translational modifications in the regulation of PRR signaling and activation of antiviral innate immune responses.

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Figure 1: Deficiency in Dnmt3a selectively impairs the production of type I interferons.
Figure 2: Myeloid Dnmt3a protects mice against viral infection.
Figure 3: Deficiency in Dnmt3a impairs IRF3 phosphorylation.
Figure 4: Dnmt3a maintains HDAC9 expression.
Figure 5: Dnmt3a promotes IFN-β production by HDAC9.
Figure 6: HDAC9 interacts with TBK1 via the HDAC9 deacetylase domain.
Figure 7: HDAC9 directly enhances activation of the kinase activity of TBK1.
Figure 8: Deacetylation of Lys241 is critical for the kinase activity of TBK1.

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Acknowledgements

We thank J. Zhu and N. Wang for mass-spectrometry analysis; Z. Chen (University of Texas Southwestern Medical Center) for the L929-shSTING cell line; B. Sun (Chinese Academy of Sciences) for SeV; and Q. Li (Chinese Academy of Medical Sciences) for HSV-1 virus (Kos strain). Supported by the National Key Basic Research Program of China (2013CB530502) and National Natural Science Foundation of China (31390431, 31370864 and 31200654).

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Author notes

  1. Xia Li, Qian Zhang and Yuanyuan Ding: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China

    Xia Li, Yuanyuan Ding, Yiqi Liu, Dezhi Zhao, Qingqing Wang & Xuetao Cao

  2. National Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China

    Xia Li, Qian Zhang, Kai Zhao & Xuetao Cao

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

    Qian Zhang, Qicong Shen, Xingguang Liu, Xuhui Zhu, Nan Li & Xuetao Cao

  4. Advanced Translational Medicine Institute, Tongji University, Shanghai, China

    Zhongyi Cheng

  5. Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, California, USA

    Guoping Fan

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Contributions

X. Li, Q.Z. Y.D., Y.L., D.Z., K.Z., Q.S., X. Liu, X.Z., N.L. and Q.W. performed the experiments; Q.Z. established the DNA methylomes and performed bioinformatics analysis; Z.C. did mass-spectrometry analysis; G.F. provided Dnmt3afl/fl mice; X.C. designed and supervised the research; and X.C., X. Li, Q.Z. and Q.W. analyzed data and wrote the manuscript.

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Correspondence to Qingqing Wang or Xuetao Cao.

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Integrated supplementary information

Supplementary Figure 1 Dnmt3afl/flLyz2-Cre mice have no abnormal differentiation of macrophages.

(a) Immunoblot analysis of Dnmt3a expression in mouse peritoneal macrophages from Dnmt3afl/flLyz2-cre and Dnmt3afl/fl mice stimulated with LPS for the indicated time. (b) Cell counts of peritoneal macrophages in Dnmt3afl/flLyz2-cre and Dnmt3afl/fl mice. (c and d) FACS analysis of F4/80, CD11b expression in Dnmt3afl/flLyz2-cre and Dnmt3afl/fl peritoneal macrophages. Data are representative of three independent experiments with similar results (a,c,d) or are from three independent experiments (b; means ± s.e.m.).

Supplementary Figure 2 Knockdown of Dnmt3a impairs TBK1-dependent production of type I interferons.

(a) Q-PCR analysis of Dnmt3a mRNA expression in peritoneal macrophages 48hr after transfection with Dnmt3a siRNA. (b) Immunoblot analysis of Dnmt3a expression in peritoneal macrophages treated as in a. (c) Q-PCR analysis of IFN-β, IFN-a, TNF and IL-6 mRNA expression in Dnmt3a-knockdown peritoneal macrophages infected with VSV, SeV, HSV-1 for 8h or analysis of IFN-β, IFN-a, TNF mRNA expression in Dnmt3a-knockdown peritoneal macrophages stimulated with LPS, Poly(I:C), CpG ODN for 2h, or analysis of IL-6 mRNA expression in Dnmt3a-knockdown peritoneal macrophages stimulated with LPS, Poly(I:C), CpG ODN for 4h. (d) ELISA assay of IFN-β, IFN-a, TNF and IL-6 in supernatants of Dnmt3a-knockdown peritoneal macrophages infected with VSV, SeV, HSV-1 for 12h or stimulated with LPS, Poly(I:C), CpG ODN for 8h. (e) Q-PCR analysis of IFN-β, IFN-a mRNA expression in L929 cells stably expressing a shRNA against GFP or STING transfected with a shRNA against Dnmt3a (shDnmt3a) or Control (shCtrl) and 36hr later infected with VSV, SeV, HSV-1 for 8h. * P < 0.01. (two-tailed Student’s t-test). Data are from three independent experiments (a,c,d,e; means ± s.e.m.) or are representative of three independent experiments with similar results (b).

Supplementary Figure 3 Dnmt3a does not directly regulate the transcription of genes encoding type I interferons.

(a) ChIP analysis of the binding of IRF3 or Dnmt3a to the Ifnb1 promoter in peritoneal macrophages infected with VSV for the indicated time. IgG was used as control. (b) MeDIP analysis of the DNA methylation level of the Ifnb1 promoter in peritoneal macrophages infected with VSV for the indicated time. Data are from three independent experiments (means ± s.e.m.).

Supplementary Figure 4 Knockdown of Dnmt3a selectively impairs phosphorylation of IRF3 in response to innate stimuli.

(a,b) Immunoblot analysis of phosphorylated (p-) or total proteins in lysates of Dnmt3a-knockdown peritoneal macrophages infected with VSV or stimulated with LPS for the indicated time. Quantification of relative the protein presented levels is shown in the bottom panel. Numbers below lanes (top) indicate densitometry of the protein presented relative to β-actin expression in that same lane (below). (c,d) Immunoblot analysis of phosphorylated (p-) or total proteins in Dnmt3afl/flLyz2-cre and Dnmt3afl/fl peritoneal macrophages infected with VSV or stimulated with LPS for the indicated time. (e,f) Immunoblot analysis of phosphorylated (p-) or total proteins in lysates of Dnmt3a-knockdown peritoneal macrophages infected with VSV or stimulated with LPS for the indicated time. Data are representative of three independent experiments with similar results.

Supplementary Figure 5 Knockdown of HDAC9 does not inhibit the expression of TNF mRNA or IL-6 mRNA in macrophages.

(a) Q-PCR analysis of HDAC9 mRNA expression in peritoneal macrophages transfected with HDAC9 siRNA. (b) Immunoblot analysis of HDAC9 expression in peritoneal macrophages transfected as in (a). (c) Q-PCR analysis of IFN-β, TNF and IL-6 mRNA expression in HDAC9-knockdown peritoneal macrophages infected with VSV, or stimulated with LPS, cGAMP for the indicated time. * P < 0.01. (two-tailed Student’s t-test). Data are from three independent experiments (a,c; means ± s.e.m.) or are representative of three independent experiments with similar results (b).

Supplementary Figure 6 Dnmt3a does not affect the polyubiquitination of TBK1 in macrophages.

(a) Immunoblot analysis of K63-linked polyubiquitination of endogenous TBK1 in Dnmt3a-deficient and control peritoneal macrophages infected with VSV for 4 hours. (b) Immunoblot analysis of polyubiquitination of TBK1 in the HEK293T cells transiently transfected for 48 h with various combinations of tagged vectors (above lanes), followed by immunoprecipitation with anti-Flag or anti-HA agarose or analysis without immunoprecipitation. Data are representative of three independent experiments with similar results.

Supplementary Figure 7 Specificity of the antibody to TBK1 acetylated at Lys241.

Dot immunoblot analysis of K241 acetylation of TBK1 by using antibody specifically recognizing indicated peptide with acetylated K241 of TBK1 (TBK1 K241 Ace peptide) or pan anti-acetyl lysine antibody. Dot immunoblot analysis of non-acetylated K241 of TBK1 by using antibody recognizing the indicated peptide (TBK1 K241 control peptide) is the loading control. Data are representative of three independent experiments with similar results.

Supplementary Figure 8 Working model of Dnmt3a in promoting the production of type I interferons.

Dnmt3a enhances TLR3/4 and virus-induced type I IFN production by increasing TBK1 kinase activity through upregulating HDAC9 and promoting HDAC9-mediated deacetylation of TBK1.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 6–9 (PDF 1766 kb)

Supplementary Table 1

Genes with significant expression variation in Dnmt3a-knockdown peritoneal macrophages in microarray data (XLSX 27 kb)

Supplementary Table 2

Genes with significant expression variation in Dnmt3a-deficient peritoneal macrophages in RNA-seq data (XLSX 9 kb)

Supplementary Table 3

DMR location (XLSX 39 kb)

Supplementary Table 4

Genes with significant expression variation in HDAC9-knockdown peritoneal macrophages in microarray data (XLSX 19 kb)

Supplementary Table 5

Mass spectrometry analysis of lysine acetylated residues of mouse TBK1 in Dnmt3a-deficient peritoneal macrophages infected with VSV (XLSX 10 kb)

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Li, X., Zhang, Q., Ding, Y. et al. Methyltransferase Dnmt3a upregulates HDAC9 to deacetylate the kinase TBK1 for activation of antiviral innate immunity. Nat Immunol 17, 806–815 (2016). https://doi.org/10.1038/ni.3464

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