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

• Published in: Nature immunology Vol. 17; no. 7; pp. 806 - 815
• Main Authors: Li, Xia, Zhang, Qian, Ding, Yuanyuan, Liu, Yiqi, Zhao, Dezhi, Zhao, Kai, Shen, Qicong, Liu, Xingguang, Zhu, Xuhui, Li, Nan, Cheng, Zhongyi, Fan, Guoping, Wang, Qingqing, Cao, Xuetao
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2016; Nature Publishing Group
• Subjects: 13/21; 631/250/262/2106; 692/699/255/2514; 96/95; Acetylation; Analysis; Animals; Biomedicine; Cellular signal transduction; DNA (Cytosine-5-)-Methyltransferases - metabolism; Dosage and administration; Epigenesis, Genetic; Gene expression; Genetic aspects; Health aspects; HEK293 Cells; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Immune response; Immunity, Innate; Immunology; Infectious Diseases; Interferon; Interferon Type I - metabolism; Macrophages; Macrophages - immunology; Macrophages - virology; Male; Methyltransferases; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pattern recognition receptors; Properties; Protein-Serine-Threonine Kinases - metabolism; RAW 264.7 Cells; Receptors, Pattern Recognition - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Rhabdoviridae Infections - immunology; Signal Transduction; Tumor necrosis factor; Vesicular stomatitis Indiana virus - immunology
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.3464

The DNA methyltransferase Dnmt3a has not been studied in innate immunity. Cao and colleagues show that Dnmt3a enhances antiviral responses via a non-canonical mechanism to activate the kinase TBK1 and the production of type I interferons in macrophages. 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.