Chaperone-and PTM-mediated activation of IRF1 tames radiation-induced cell death and the inflammatory response  

作　　者：Fenghao Geng Jianhui Chen Bin Song Zhicheng Tang Xiaoqian Li Shuaijun Zhang Tingyi Yang Yulan Liu Wei Mo Yining Zhang Chuntang Sun Lei Tan Wenling Tu Daojiang Yu Jianping Cao Shuyu Zhang 

机构地区：[1]Laboratory of Radiation Medicine,Key Laboratory of Birth Defects and Related Diseases of Women and Children(Sichuan University),Ministry of Education,West China Second University Hospital,Sichuan University,Chengdu,610041,China [2]Department of Radiation Medicine,West China School of Basic Medical Sciences&Forensic Medicine,Sichuan University,Chengdu,610041,China [3]School of Radiation Medicine and Protection,State Key Laboratory of Radiation Medicine,Soochow University,Suzhou,215123,China [4]The Second Affiliated Hospital of Chengdu Medical College,China National Nuclear Corporation 416 Hospital,Chengdu,610051,China [5]NHC Key Laboratory of Nuclear Technology Medical Transformation,Mianyang Central Hospital,Mianyang,621099,China

出　　处：《Cellular & Molecular Immunology》2024年第8期856-872,共17页中国免疫学杂志（英文版）

基　　金：National Natural Science Foundation of China 82073477(SZ),32071238(DY)and 82203973(FG);Scientific Fund for Distinguished Young Scholars in Sichuan Province 2022JDJQ0051(SZ)and 2022NSFSC0797(CS)and Young Talent Project of China National Nuclear Corporation(SZ).

摘　　要：The key role of structural cells in immune modulation has been revealed with the advent of single-cell multiomics,but the underlying mechanism remains poorly understood.Here,we revealed that the transcriptional activation of interferon regulatory factor 1(IRF1)in response to ionizing radiation,cytotoxic chemicals and SARS-CoV-2 viral infection determines the fate of structural cells and regulates communication between structural and immune cells.Radiation-induced leakage of mtDNA initiates the nuclear translocation of IRF1,enabling it to regulate the transcription of inflammation-and cell death-related genes.Novel posttranslational modification(PTM)sites in the nuclear localization sequence(NLS)of IRF1 were identified.Functional analysis revealed that mutation of the acetylation site and the phosphorylation sites in the NLS blocked the transcriptional activation of IRF1 and reduced cell death in response to ionizing radiation.Mechanistically,reciprocal regulation between the single-stranded DNA sensors SSBP1 and IRF1,which restrains radiation-induced and STING/p300-mediated PTMs of IRF1,was revealed.In addition,genetic deletion or pharmacological inhibition of IRF1 tempered radiation-induced inflammatory cell death,and radiation mitigators also suppressed SARS-CoV-2 NSP-10-mediated activation of IRF1.Thus,we revealed a novel cytoplasm-oriented mechanism of IRF1 activation in structural cells that promotes inflammation and highlighted the potential effectiveness of IRF1 inhibitors against immune disorders.

关 键 词：Interferon regulatory factor 1(IRF1) Ionizing radiation Nuclear translocation Posttranslational modification(PTM) Transcription regulation 

分 类 号：R392[医药卫生—免疫学]