Nuclear factor kappa B p65 subunit–Bromodomain and extra-terminal domain protein interaction (NF-κB p65–BET interaction)

The NF-κB p65–BET interaction is a critical molecular assembly that links the NF-κB signaling pathway to the epigenetic control of gene expression. Specifically, the p65 (RELA) subunit of NF-κB, upon acetylation at Lysine 310, recruits Bromodomain and Extra-Terminal (BET) proteins, primarily BRD4, to the promoters and enhancers of target genes (Huang et al., 2009; PubMed: 19234457). This interaction facilitates the recruitment of the Positive Transcription Elongation Factor b (P-TEFb) complex, which phosphorylates RNA polymerase II to trigger transcriptional elongation of pro-inflammatory and oncogenic genes (Zou et al., 2014; PubMed: 24403024). In pathological contexts such as hematological malignancies and chronic inflammatory disorders, this interaction is often hyperactive, leading to the overproduction of cytokines like IL-6 and IL-8 (Belkina & Denis, 2012; PubMed: 22903144). Small-molecule BET inhibitors (BETi) target this interaction by binding to the acetyl-lysine recognition pockets of BET proteins, thereby displacing them from p65 and suppressing the downstream transcriptional program (Filippakopoulos et al., 2010; PubMed: 20871596). While BET inhibitors show promise in treating cancer and inflammation, their clinical development faces challenges due to dose-limiting toxicities such as thrombocytopenia and gastrointestinal issues (Doroshow et al., 2017; PubMed: 28842354).

Other names

RELA–BRD4 interactionNF-kappaB–BET axisp65–BRD4 complexNF-κB–BET protein-protein interaction

Small-molecule inhibitors bind to the bromodomains of BET proteins, competitively inhibiting their interaction with acetylated lysine residues on the p65 subunit of NF-κB, which prevents the recruitment of transcriptional machinery to target genes.