Small cytosolic double-stranded DNA represses cyclic GMP-AMP synthase activation and induces autophagy

作者全名："Liu, Yao; Chen, Xiao; Zhao, Yuemei; Wang, Xing-Yue; Luo, Yu-Wei; Chen, Lina; Wang, Weiyun; Zhong, Shouhui; Hu, Meizhen; Dai, Zhizheng; Jiang, Jiayu; Wang, Xin; Ji, Hongyu; Cheng, Xiao-Xiao; Zheng, Anqi; Zuo, Jiwei; Liu, Hui; Ma, Di; Luo, Zhicheng; Cao, Fang; Hu, Shanshan; Huang, Ai-Long; Tang, Kai-Fu"

作者地址："[Liu, Yao; Luo, Yu-Wei; Hu, Meizhen; Dai, Zhizheng; Wang, Xin; Ji, Hongyu; Cao, Fang; Huang, Ai-Long; Tang, Kai-Fu] Chongqing Med Univ, Minist Educ, Key Lab Mol Biol Infect Dis, Chongqing 400016, Peoples R China; [Chen, Xiao; Zhao, Yuemei; Wang, Xing-Yue; Chen, Lina; Wang, Weiyun; Zhong, Shouhui; Jiang, Jiayu; Cheng, Xiao-Xiao; Zheng, Anqi; Zuo, Jiwei; Liu, Hui; Ma, Di; Luo, Zhicheng; Hu, Shanshan] Wenzhou Med Univ, Affiliated Hosp 1, Key Lab Diag & Treatment Severe Hepatopancreat Dis, Wenzhou 325015, Zhejiang, Peoples R China; [Chen, Xiao] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Key Lab Precis Diag & Treatment Hepatobiliary & Pa, Hangzhou 310009, Zhejiang, Peoples R China"

通信作者："Huang, AL; Tang, KF (通讯作者)，Chongqing Med Univ, Minist Educ, Key Lab Mol Biol Infect Dis, Chongqing 400016, Peoples R China."

来源：CELL REPORTS

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001054924300001

JCR分区：Q1

影响因子：7.5

年份：2023

卷号：42

期号：8

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a major mediator of inflammation following stimulation with >45 bp double-stranded DNA (dsDNA). Herein, we identify a class of similar to 20-40 bp small cytosolic dsDNA (scDNA) molecules that compete with long dsDNA (200-1,500 bp herring testis [HT]-DNA) for binding to cGAS, thus repressing HT-DNA-inducedcGASactivation. ThescDNA promotes cGAS and Beclin-1 interaction, releasing Rubicon, a negative regulator of phosphatidylinositol 3-kinase class III (PI3KC3), from the Beclin-1-PI3KC3 complex. This leads to PI3KC3 activation and induces autophagy, causing degradation of STING and long cytosolic dsDNA. Moreover, DNA damage decreases, and autophagy inducers increase scDNA levels. scDNA transfection and treatment with autophagy inducers attenuate DNA damage-induced cGAS activation. Thus, scDNA molecules serve as effective brakes for cGAS activation, preventing excessive inflammatory cytokine production following DNAdamage. Our findings may have therapeutic implications for cytosolic DNA-associated inflammatory diseases."

基金机构：Chongqing Medical University Program for Youth Innovation in Future Medicine; [W0084]

基金资助正文："We thank Dr. Peng Huang at the Electron Microscopy Core Facility of Chongq-ing Medical University for training in electron microscopy sample preparation and image processing. This work was supported by the National Natural Sci-ence Foundation of China (grant nos. 81972648, 82172915, and 81773011)r and the Chongqing Medical University Program for Youth Innovation in Future Medicine (grant no. W0084) ."