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

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.