Epigenetic regulation of the expression of Il12 and Il23 and autoimmune inflammation by the deubiquitinase Trabid

• Published in: Nature immunology Vol. 17; no. 3; pp. 259 - 268
• Main Authors: Jin, Jin, Xie, Xiaoping, Xiao, Yichuan, Hu, Hongbo, Zou, Qiang, Cheng, Xuhong, Sun, Shao-Cong
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2016; Nature Publishing Group
• Subjects: 38/109; 42/41; 42/89; 45/15; 631/250/2502/2170; 631/250/38; 631/250/516; 96/31; 96/95; Animals; Biomedicine; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation; Chromatin Immunoprecipitation; Dendritic Cells - immunology; Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Epigenesis, Genetic; Flow Cytometry; Gene Expression Regulation; Gene Knockdown Techniques; Immunoblotting; Immunology; Immunoprecipitation; Infectious Diseases; Interleukin-12 - genetics; Interleukin-12 - immunology; Interleukin-23 - genetics; Interleukin-23 - immunology; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Mice; Reverse Transcriptase Polymerase Chain Reaction; RNA-Binding Proteins - genetics; RNA-Binding Proteins - immunology; Signal Transduction; Toll-Like Receptors - metabolism; Ubiquitin-Specific Proteases - genetics; Ubiquitin-Specific Proteases - immunology; Zinc Fingers - genetics; Zinc Fingers - immunology
• DOI: 10.1038/ni.3347
• ISSN: 1529-2908; 1529-2916

Sun and colleagues show that the deubiquitinase Trabid mediates the TLR-induced deubiqutination and stabilization of the histone demethylase Jmjd2d at the Il12 and Il23 promoters in dendritic cells. The proinflammatory cytokines interleukin 12 (IL-12) and IL-23 connect innate responses and adaptive immune responses and are also involved in autoimmune and inflammatory diseases. Here we describe an epigenetic mechanism for regulation of the genes encoding IL-12 ( Il12a and Il12b ; collectively called ' Il12 ' here) and IL-23 ( Il23a and Il12b ; collectively called ' Il23 ' here) involving the deubiquitinase Trabid. Deletion of Zranb1 (which encodes Trabid) in dendritic cells inhibited induction of the expression of Il12 and Il23 by Toll-like receptors (TLRs), which impaired the differentiation of inflammatory T cells and protected mice from autoimmune inflammation. Trabid facilitated TLR-induced histone modifications at the promoters of Il12 and Il23 , which involved deubiqutination and stabilization of the histone demethylase Jmjd2d. Our findings highlight an epigenetic mechanism for the regulation of Il12 and Il23 and establish Trabid as an innate immunological regulator of inflammatory T cell responses.