Disulfiram ameliorates STING/MITA-dependent inflammation and autoimmunity by targeting RNF115  

作　　者：Zhi-Dong Zhang Chang-Rui Shi Fang-Xu Li Hu Gan Yanhong Wei Qianhui Zhang Xin Shuai Min Chen Yu-Lin Lin Tian-Chen Xiong Xiaoqi Chen Bo Zhong Dandan Lin 

机构地区：[1]Department of Gastrointestinal Surgery,Medical Research Institute,Frontier Science Center of Immunology and Metabolism,Zhongnan Hospital of Wuhan University,Wuhan University,Wuhan,430071,China [2]Department of Virology,College of Life Sciences,Wuhan University,Wuhan,430072,China [3]TaiKang Center for Life and Medical Sciences,Wuhan University,Wuhan,430071,China [4]Wuhan Research Center for Infectious Diseases and Cancer,Chinese Academy of Medical Sciences,Wuhan,430071,China [5]Department of Rheumatology and Immunology,Zhongnan Hospital of Wuhan University,Wuhan,430071,China [6]Cancer Center,Renmin Hospital of Wuhan University,Wuhan,430060,China

出　　处：《Cellular & Molecular Immunology》2024年第3期275-291,共17页中国免疫学杂志（英文版）

基　　金：supported by grants from the National Key Research and Development Program of China(Grant Nos.2022YFC3401500 and 2023YFC2306100);the Natural Science Foundation of China(Grant Nos.31930040,32070900,82000670,32270951,32200710,and 823B1006);the Fundamental Research Funds for the Central Universities(Grant Nos.2042022kf1187,2042022kf1123 and 2042022dx0003);the Major Scientific and Technological Project of Hubei Province(Grant No.2022ACA005);the Translational Medicine and Interdisciplinary Research Joint Found of Zhongnan Hospital of Wuhan University(Grant.No.ZNJC202218);the Non-Profit Central Research Institute Fund of the Chinese Academy of Medical Sciences(Grant No.2020PT320-004).

摘　　要：STING(also known as MITA)is an adaptor protein that mediates cytoplasmic DNA-triggered signaling,and aberrant activation of STING/MITA by cytosolic self-DNA or gain-of-function mutations causes severe inflammation.Here,we show that STING-mediated inflammation and autoimmunity are promoted by RNF115 and alleviated by the RNF115 inhibitor disulfiram(DSF).Knockout of RNF115 or treatment with DSF significantly inhibit systemic inflammation and autoimmune lethality and restore immune cell development in Trex1^(–/–)mice and STING^(N153S/WT) bone marrow chimeric mice.In addition,knockdown or pharmacological inhibition of RNF115 substantially downregulate the expression of IFN-α,IFN-γand proinflammatory cytokines in PBMCs from patients with systemic lupus erythematosus(SLE)who exhibit high concentrations of dsDNA in peripheral blood.Mechanistically,knockout or inhibition of RNF115 impair the oligomerization and Golgi localization of STING in various types of cells transfected with cGAMP and in organs and cells from Trex1^(–/–)mice.Interestingly,knockout of RNF115 inhibits the activation and Golgi localization of STINGN153S as well as the expression of proinflammatory cytokines in myeloid cells but not in endothelial cells or fibroblasts.Taken together,these findings highlight the RNF115-mediated cell type-specific regulation of STING and STINGN153S and provide potential targeted intervention strategies for STING-related autoimmune diseases.

关 键 词：STING/MITA DISULFIRAM RNF115 SLE AUTOIMMUNITY 

分 类 号：R392[医药卫生—免疫学]