C-terminal binding protein 2 interacts with JUNB to control macrophage inflammation

Although acute inflammatory responses are critical for survival, chronic inflammation is a leading cause of disease and mortality worldwide. Nevertheless, our mechanistic understanding of pathogenesis is still limited and precise treatment options are lacking. Here, we investigate the role of the transcriptional co-repressors C-terminal binding protein (CTBP) 1 and 2 in murine and human macrophage activation using loss-of-function models to show that CTBP2 but not CTBP1 controls inflammatory gene expression. We find that CTBP2 occupies <i>cis</i>-regulatory elements of inflammatory genes together with the transcription factors NF-κB and AP-1 and forms a co-repressor complex. Rescue of <i>Ctbp1/2</i> double knockout cells with WT, oligomeric CTBP2 attenuates inflammatory responses, whereas a monomeric mutant does not. Differential profiling of CTBP2's WT and monomeric interactome confirms oligomer-specific interactions with multiple repressors. Conversely, monomers retain the ability to interact with AP-1 and RNA polymerase II, boosting gene expression. Our findings point to an important function for CTBP2 in fine-tuning inflammatory gene expression, potentially unveiling novel therapeutic targets for the treatment of inflammatory diseases.