Cbx4 SUMOylates BRD4 to regulate the expression of inflammatory cytokines in post-traumatic osteoarthritis

Abstract

Brominated domain protein 4 (BRD4) is a chromatin reader known to exacerbate the inflammatory response in post-traumatic osteoarthritis (PTOA) by controlling the expression of inflammatory cytokines. However, the extent to which this regulatory effect is altered after BRD4 translation remains largely unknown. In this study, we showed that the E3 SUMO protein ligase CBX4 (Cbx4) is involved in the SUMO modification of BRD4 to affect its ability to control the expression of the proinflammatory genes IL-1β, TNF-α, and IL-6 in synovial fibroblasts. Specifically, Cbx4-mediated SUMOylation of K1111 lysine residues prevents the degradation of BRD4, thereby activating the transcriptional activities of the IL-1β, TNF-α and IL-6 genes, which depend on BRD4. SUMOylated BRD4 also recruits the multifunctional methyltransferase subunit TRM112-like protein (TRMT112) to further promote the processing of proinflammatory gene transcripts to eventually increase their expression. In vivo, treatment of PTOA with a Cbx4 inhibitor in rats was comparable to treatment with BRD4 inhibitors, indicating the importance of SUMOylation in controlling BRD4 to alleviate PTOA. Overall, this study is the first to identify Cbx4 as the enzyme responsible for the SUMO modification of BRD4 and highlights the central role of the Cbx4-BRD4 axis in exacerbating PTOA from the perspective of inflammation. In research on post-traumatic osteoarthritis, scientists found a lack of knowledge on how inflammation worsens the disease. Researchers found that the protein BRD4, when altered by a process called SUMOylation, is crucial in causing inflammation in PTOA. The study used human tissue and rats to see how blocking BRD4 and a related protein, Cbx4, affects inflammation and disease development. The study involved 45 rats and examined how these proteins contribute to PTOA, using various techniques to understand their roles in inflammation. The findings showed that blocking BRD4 and Cbx4 lessened inflammation and joint damage in rats with PTOA. Specifically, treatments targeting these proteins lowered inflammation markers and improved joint health. The team concluded that the BRD4-Cbx4 interaction is a major factor in PTOA inflammation and progression, marking a significant step in understanding the disease’s molecular workings. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.