Macrophage USP14 suppresses Wnt/β-catenin signaling via NLK deubiquitination to enhance immune response

Macrophages are key immune cells that regulate the body's immune response by promoting the release of inflammatory cytokines upon recognition of both endogenous and exogenous pathogens. USP14, a critical Deubiquitinase, plays a vital role in various cellular processes, especially in modulating immune responses. This study aims to investigate the role of USP14 in regulating macrophage immune responses. USP14 overexpression and knockdown were performed in RAW264.7 cells and mouse bone marrow macrophages via plasmid transfection and lentiviral Infection, respectively. Our research demonstrates that USP14 overexpression amplified the LPS-induced inflammatory response and promoted macrophage migration, whereas USP14 knockdown produced the opposite effects. USP14 interacts with NLK, thereby attenuating Wnt/β-catenin signaling and concurrently activating the NF-κB pathway in macrophages. USP14 facilitates the deubiquitination of NLK, thereby stabilizing its activity. Moreover, the USP14 inhibitor IU1 reduces the LPS-induced inflammatory response in macrophages. Mechanistically, macrophage USP14 facilitates the deubiquitination of NLK, thereby maintaining its activity, inhibiting the Wnt/β-catenin pathway, activating the NF-κB pathway, and enhancing the cellular immune response.

Immune response; Macrophage; NLK; USP14; β-Catenin.