Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis

Abstract

Systemic lupus erythematosus (SLE), a severe autoimmune disorder, is characterized by systemic inflammatory response, autoantibody accumulation and damage to organs. The dysregulation of double-negative (DN) T cells is considered as a crucial commander during SLE. Neddylation, a significant type of protein post-translational modification (PTM), has been well-proved to regulate T cell-mediated immune response. However, the function of neddylation in SLE is still unknown. Here, we reported that neddylation inactivation with MLN4924, a specific inhibitor of NEDD8-activating enzyme E1 (NAE1), or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development. Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells, contributing to the apoptosis of the accumulated DN T cells in lupus mice. Then double knockout (KO) lupus-prone mice (Ube2m -/- Bim -/- lpr) were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression. Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression. Clinically, we also found that in SLE patients, the proportion of DN T cells was raised and their apoptosis was reduced. Moreover, compared to healthy groups, SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels. Meantime, the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients. Altogether, our findings provide the direct evidence about the function of neddylation during lupus, suggesting a promising therapeutic approach for this disease.