SIRT3-SUMO regulated Treg cell differentiation and asthma development by mediating N-glycosylation through the FAO pathway

Asthma, a chronic inflammatory disease, has a high disability rate, which greatly increases the disease burden. T cells are pivotal in the pathogenesis of asthma, and Treg cells, due to their role in maintaining immune system balance, represent a promising avenue for therapeutic intervention. Initial weighted correlation network analysis (WGCNA) analysis of asthma-related datasets indicates that N-glycosylation plays a critical role in asthma development. The establishment of an OVA-sensitized asthma model, along with the isolation of naive CD4⁺ T cells and subsequent in vitro induction of Treg cell differentiation, further underscores the significance of N-glycosylation in the Treg cell differentiation of asthma-related Treg cells. Employing immunofluorescence, flow cytometry, and Western blot techniques revealed that SIRT3-SUMO is instrumental in regulating N-glycosylation-mediated Treg cells development. Mechanistically, overexpression and deSUMOylation of SIRT3 enhance the expression levels of CPT1 and VLCAD to promote fatty acid oxidation (FAO), thereby increasing intracellular acetyl-CoA concentrations. Acetyl-CoA subsequently facilitates the synthesis of N-glycosylation substrates via the hexosamine biosynthetic pathway (HBP), promoting Treg cell differentiation. Ultimately, our in vivo experiments demonstrate that SIRT3-SUMO modulates asthma progression by influencing Treg cells differentiation; thus, augmenting Treg cells populations can inhibit Th2-type and non-Th2-type asthmatic developments. These findings elucidate mechanisms underlying Treg cell differentiation and provide theoretical foundations for targeted therapies aimed at enhancing Treg cells for asthma management.