The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation

• Published in: Nature immunology Vol. 15; no. 3; pp. 239 - 247
• Main Authors: Tiruppathi, Chinnaswamy, Soni, Dheeraj, Wang, Dong-Mei, Xue, Jiaping, Singh, Vandana, Thippegowda, Prabhakar B, Cheppudira, Bopaiah P, Mishra, Rakesh K, DebRoy, Auditi, Qian, Zhijian, Bachmaier, Kurt, Zhao, You-Yang, Christman, John W, Vogel, Stephen M, Ma, Averil, Malik, Asrar B
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-03-2014; Nature Publishing Group
• Subjects: 13; 13/21; 13/89; 38; 38/15; 692/699; Acute Lung Injury - genetics; Acute Lung Injury - metabolism; Animals; Biomedicine; Chromatin Immunoprecipitation; Cysteine Endopeptidases; Disease Models, Animal; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; Endotoxins; Gene expression; Gene Expression Regulation - immunology; Genetic aspects; Genetic research; Immunoblotting; Immunology; Infectious Diseases; Inflammation - genetics; Inflammation - metabolism; Intracellular Signaling Peptides and Proteins - biosynthesis; Intracellular Signaling Peptides and Proteins - genetics; Kv Channel-Interacting Proteins - metabolism; Medical treatment; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - genetics; NF-kappa B - metabolism; Properties; Real-Time Polymerase Chain Reaction; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Transcription factors; Tumor Necrosis Factor alpha-Induced Protein 3; Ubiquitin-proteasome system; Ubiquitin-Protein Ligases - biosynthesis; Ubiquitin-Protein Ligases - genetics; Upstream Stimulatory Factors - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/ni.2823

The transcriptional repressor DREAM is involved in pain sensing. Tiruppathi and colleagues show that it is also involved in innate signaling by regulating the anti-inflammatory deubiquitinase A20.
Here we found that the transcription repressor DREAM bound to the promoter of the gene encoding A20 to repress expression of this deubiquitinase that suppresses inflammatory NF-κB signaling. DREAM-deficient mice displayed persistent and unchecked A20 expression in response to endotoxin. DREAM functioned by transcriptionally repressing A20 through binding to downstream regulatory elements (DREs). In contrast, binding of the transcription factor USF1 to the DRE-associated E-box domain in the gene encoding A20 activated its expression in response to inflammatory stimuli. Our studies define the critical opposing functions of DREAM and USF1 in inhibiting and inducing A20 expression, respectively, and thereby the strength of NF-κB signaling. Targeting of DREAM to induce USF1-mediated A20 expression is therefore a potential anti-inflammatory strategy for the treatment of diseases associated with unconstrained NF-κB activity, such as acute lung injury.