The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation.
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.
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Chinnaswamy
C
Tiruppathi
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Dheeraj
D
Soni
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Dong-Mei
DM
Wang
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Jiaping
J
Xue
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Vandana
V
Singh
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Prabhakar B
PB
Thippegowda
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Bopaiah P
BP
Cheppudira
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Rakesh K
RK
Mishra
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Auditi
A
Debroy
Department of Hematology/Oncology, College of Medicine, University of Illinois, Chicago, Illinois, USA.
Zhijian
Z
Qian
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Kurt
K
Bachmaier
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
You-Yang
YY
Zhao
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
John W
JW
Christman
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Stephen M
SM
Vogel
Department of Medicine, School of Medicine, University of California at San Francisco, San Francisco, California, USA.
Averil
A
Ma
Department of Pharmacology and the Center for Lung and Vascular Biology, University of Illinois, Chicago, Illinois, USA.
Asrar B
AB
Malik
D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism; D000818:Animals; D047369:Chromatin Immunoprecipitation; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000276:immunology; D015151:Immunoblotting; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D051605:Kv Channel-Interacting Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics; D051720:Upstream Stimulatory Factors / Q000378:metabolism*
C496756:Csen protein, mouse; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051605:Kv Channel-Interacting Proteins; D016328:NF-kappa B; D012097:Repressor Proteins; D051720:Upstream Stimulatory Factors; C497183:Usf1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse