NF-κB c-Rel Dictates the Inflammatory Threshold by Acting as a Transcriptional Repressor.

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Department of Pathology, School of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, 6526, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106, USA; Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; The Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. Electronic address:

Published: March 2020

NF-κB/Rel family of transcription factors plays a central role in initiation and resolution of inflammatory responses. Here, we identified a function of the NF-κB subunit c-Rel as a transcriptional repressor of inflammatory genes. Genetic deletion of c-Rel substantially potentiates the expression of several TNF-α-induced RelA-dependent mediators of inflammation. v-Rel, the viral homologue of c-Rel, but not RelB, also possesses this repressive function. Mechanistically, we found that c-Rel selectively binds to the co-repressor HDAC1 and competitively binds to the DNA mediating HDAC1 recruitment to the promoters of inflammatory genes. A specific point mutation at tyrosine in c-Rel's DNA-binding domain, for which a missense single nucleotide variation (Y25H) exists in humans, completely abrogated its ability to bind DNA and repress TNF-α-induced, RelA-mediated transcription. Our findings reveal that the transactivator NF-κB subunit c-Rel also plays a role as a transcriptional repressor in the maintenance of inflammatory homeostasis.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031323PMC
http://dx.doi.org/10.1016/j.isci.2020.100876DOI Listing

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