iScience 2020 Mar 1;23(3):100876. Epub 2020 Feb 1.
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:
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.