MDA5 regulates BCR signaling and B-cell function via NF-κB-mediated DNM1

Melanoma Differentiation-Associated gene 5 (MDA5) serves as a pattern recognition receptor (PRR) that identifies pathogen-associated molecular patterns (PAMPs), making it instrumental in antiviral defense. However, its non-canonical role in adaptive immunity, particularly in regulating B-cell immune functions, is poorly characterized. Here, we demonstrate that MDA5 is critical for the marginal zone (MZ) B-cell differentiation, B-cell receptor (BCR) signal transduction, and cytoskeletal dynamics. We determined that the MDA5-NF-κB-DNM1 axis governs actin polymerization and that this impairment in Mda5 knockout (KO) B cells can be rescued by the treatment with the dynamin1 (DNM1) activator Bis-T-23. Furthermore, MDA5 deficiency induces metabolic perturbations in B cells, characterized by a reduced extracellular acidification rate (ECAR) and oxygen consumption rate (OCR), excessive reactive oxygen species (ROS) accumulation, and increased mitochondrial fission. Notably, taurine levels are decreased in Mda5 KO B cells, and in vitro taurine supplementation rescues impaired BCR signaling. Finally, MDA5-deficient mice exhibit a blunted humoral immune response. Overall, this study reveals the key functions and molecular mechanisms of MDA5 in B-cell differentiation, BCR signaling, and the humoral immune response.