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

作　　者：Yun Zhang Lijun Du Chenxi Wang Zhangsheng Jiang Qingchi Duan Yiping Li Zhijun Xie Zhixing He Yi Sun Lin Huang Liwei Lu Chengping Wen 

机构地区：[1]Key Laboratory of Chinese medicine rheumatology of Zhejiang Province,Research Institute of Chinese Medical Clinical Foundation and Immunology,College of Basic Medical Science,Zhejiang Chinese Medical University,Hangzhou 310053,China [2]Department of General Surgery,Sir Run Run Shaw Hospital,Zhejiang University School of Medicine,Hangzhou 310016,China [3]Cancer Institute(Key Laboratory of Cancer Prevention and Intervention,China National Ministry of Education)of the Second Affiliated Hospital and Institute of Translational Medicine,Zhejiang University School of Medicine,Hangzhou 310029,China [4]Cancer Center of Zhejiang University,Hangzhou 310029,China [5]Department of Pathology and Shenzhen Institute of Research and Innovation,The University of Hong Kong,Hong Kong,China [6]Chongqing International Institute for Immunology,Chongqing 400038,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第2期738-750,共13页信号转导与靶向治疗（英文）

基　　金：supported by Regional Innovation and Development Joint Fund of the National Foundation of China(U21A20402)to C.W.;National Natural Science Foundation of China(No.82074375);the Research Project of Zhejiang Chinese Medical University(No.2023JKZDZC01)to Y.Z.;Chongqing International Institute for Immunology(2020YJC10)to L.L.;National Natural Science Foundation of China(No.82074217)to Z.H.

摘　　要：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.

关 键 词：INACTIVATION DOUBLE finding 

分 类 号：R593.241[医药卫生—内科学]