Dissecting the functional role of SENP2 in B cells and systemic lupus erythematosus

Abstract SUMOylation is a post-translational modification that can dynamically regulate protein activity. SUMOylation involves covalent binding to a lysine residue of the target proteins, and the SUMO-specific peptidase (SENP) catalyzes deconjugation. In our laboratory, we analyzed the changes in the expression of genes involved in SUMOylation and found a significant reduction of SENP2 in peripheral navie B cells isolated from patients with SLE as compared to that from healthy donors. We thus stimulated peripheral human B cells and transfected them with siRNAs against SENP2. Our results showed a significant increase in IgG antibodies after knocking down SENP2. We also stimulated naive splenic mouse B cells with T cell-independent (TI) or T cell-dependent (TD) stimulation to examine the expression level of SENP2 after B cell activation. The results showed downregulation of SENP2 protein after TD stimulation, but not after TI stimulation. Taken together, because the increase in IgG antibodies is often due to an enhanced germinal center (GC) response, we next investigated the role of SENP2 in B-cell differentiation and SLE pathogenesis. Hence, we developed a mouse model in which Senp2is deleted in GC B cells. However, after immunization with TD stimulation, we found a reduction in the frequency of GC-B cells, plasma cells, IgG1-expressing cells, and the amount of antibody production in GC-specific Senp2knockout mice, which can be recapitulated by using an in vitro induced germinal center culture (iGB) system. We thus hypothesized that the role of SENP2 for limiting IgG production may act in early-phase before GC B cells. The exact timing and mode of action of SENP2’s activity to restrain the production of IgG will be investigated.