The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation

Chinnaswamy Tiruppathi*, Dheeraj Soni, Dong Mei Wang, Jiaping Xue, Vandana Singh, Prabhakar B. Thippegowda, Bopaiah P. Cheppudira, Rakesh K. Mishra, Auditi Debroy, Zhijian Qian, Kurt Bachmaier, You Yang Zhao, John W. Christman, Stephen M. Vogel, Averil Ma, Asrar B. Malik

*Corresponding author for this work

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)239-247
Number of pages9
JournalNature Immunology
Volume15
Issue number3
DOIs
StatePublished - Mar 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Tiruppathi, C., Soni, D., Wang, D. M., Xue, J., Singh, V., Thippegowda, P. B., Cheppudira, B. P., Mishra, R. K., Debroy, A., Qian, Z., Bachmaier, K., Zhao, Y. Y., Christman, J. W., Vogel, S. M., Ma, A., & Malik, A. B. (2014). The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation. Nature Immunology, 15(3), 239-247. https://doi.org/10.1038/ni.2823