IGF2BP2 condensates stabilize DOK3 to negatively regulate inflammatory responses

Negative regulators are crucial for maintaining immune homeostasis, yet the complexities of their regulatory mechanisms are not fully elucidated. In this study, we reveal that IGF2BP2, an m6A reader protein, orchestrates the formation of phase-separated condensates dependent on G3BP1, acting as a pivotal negative regulator of bacterial-induced inflammation. The absence of IGF2BP2 amplifies the production of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β, whereas its overexpression attenuates these inflammatory responses. Mechanistically, IGF2BP2 depletion enhances NF-κB signaling by diminishing DOK3 expression upon bacterial stimulation. Restoration of DOK3 expression in IGF2BP2-deficient cells markedly mitigates this hyper-inflammatory phenotype. Additionally, we identify m6A modifications at nucleotides 1056 and 1101 on DOK3 mRNA that facilitate its binding and stabilization by IGF2BP2. These insights provide a novel understanding of how IGF2BP2 modulates immune responses via m6A-dependent stabilization of DOK3 mRNA and highlight potential therapeutic avenues for treating inflammatory diseases.