PR003059 (Project)

Description:How pyrimidine metabolism promotes systemic autoimmunity is unknown. Here, metabolomics and 15N-amide glutamine tracing show enhanced flux through de novo pyrimidine synthesis in SLE-prone B cells. Inhibition of pyrimidine synthesis dampened SLE-prone germinal center (GC), plasma cell (PC), and antibody responses. UMPS conditional deletion revealed a B cell-intrinsic requirement of de novo pyrimidine synthesis in SLE-prone GC, PC and autoantibody responses, and kidney immune complex deposition. Conditional UMPS deletion but not short-term inhibition dampened foreign-antigen drive GC, PC, and antibody responses. Pyrimidine synthesis promotes aerobic glycolysis and oxidative phosphorylation of fatty and amino acids in SLE-prone B cells. De novo pyrimidine synthesis helps SLE-prone B cells maintain heightened metabolic state and expression of metabolic regulator cMYC. Mechanistically, mTORC1 and S6K1 downstream of TLR7 and CD40 signaling in B cells promotes pyrimidine synthesis by phosphorylating and activating CAD, a critical rate-limiting enzyme of this pathway.