Death Domain-associated Protein 6 (Daxx) Selectively Represses IL-6 Transcription through Histone Deacetylase 1 (HDAC1)-mediated Histone Deacetylation in Macrophages

• Published in: The Journal of biological chemistry Vol. 289; no. 13; pp. 9372 - 9379
• Main Authors: Yao, Zhenyu, Zhang, Qian, Li, Xia, Zhao, Dezhi, Liu, Yiqi, Zhao, Kai, Liu, Yin, Wang, Chunmei, Jiang, Minghong, Li, Nan, Cao, Xuetao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.03.2014; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylation - drug effects; Animals; Carrier Proteins - metabolism; Co-Repressor Proteins; Daxx; Epigenesis, Genetic - drug effects; HEK293 Cells; Histone Acetylation; Histone Deacetylase; Histone Deacetylase 1 - metabolism; Histones - metabolism; Humans; IL-6; Immunity, Innate - drug effects; Immunity, Innate - genetics; Immunology; Innate Immunity; Interleukin-6 - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Ligands; Lipopolysaccharide (LPS); Lipopolysaccharides - pharmacology; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Molecular Chaperones; Nuclear Proteins - metabolism; Promoter Regions, Genetic - genetics; Toll-like Receptors (TLR); Toll-Like Receptors - metabolism; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Up-Regulation - drug effects; Toll-like Receptors (TLR); Innate Immunity; Macrophages; Histone Acetylation; Daxx; IL-6; Histone Deacetylase; Lipopolysaccharide (LPS)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.533992

As a multifunctional nuclear protein, death domain-associated protein 6 (Daxx) regulates a wide range of biological processes, including cell apoptosis and gene transcription. However, the function of Daxx in innate immunity remains unclear. In our study, we show that Daxx is highly expressed in macrophages and localized in nucleus of macrophages. The expression of Daxx is significantly up-regulated by stimulation with TLR ligands LPS and poly(I:C). Silence of Daxx selectively represses IL-6 expression at transcription level in LPS-activated macrophages. Upon stimulation of LPS, Daxx specifically binds to the promoter of IL-6 and inhibits histone acetylation at IL-6 promoter region. Further mechanism analyses show that histone deacetylase 1 (HDAC1) interacts with Daxx and binds to the promoter of IL-6. Daxx silencing decreases the association of HDAC1 to IL-6 promoter. Therefore, our data reveal that Daxx selectively represses IL-6 transcription through HDAC1-mediated histone deacetylation in LPS-induced macrophages, acting as a negative regulator of IL-6 during innate immunity and potentially preventing inflammatory response because of overproduction of IL-6. Background: The role and underlying mechanism of Daxx in innate immunity remain to be investigated. Results: Daxx interacts with HDAC1 and binds to the promoter of IL-6. Daxx selectively represses IL-6 transcription through HDAC1-mediated histone deacetylation. Conclusion: Daxx selectively represses IL-6 transcription in TLR-triggered macrophages. Significance: Discovering a new negative regulator of IL-6 and providing insight to epigenetic mechanism of IL-6 production.