Small cytosolic double-stranded DNA represses cyclic GMP-AMP synthase activation and induces autophagy
Yao Liu, Xiao Chen, Yuemei Zhao, Xingyue Wang, Yuwei Luo, Lina Chen, Weiyun Wang, Shouhui Zhong, Meizhen Hu, Zhizheng Dai, Jiayu Jiang, X Wang, Hongyu Ji, Xiaoxiao Cheng, Anqi Zheng, Jiwei Zuo, Hui Liu, Di Ma, Zhicheng Luo, Fang Cao, Shanshan Hu, Ailong Huang, Kai‐Fu Tang
Abstract
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 ∼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-induced cGAS activation. The scDNA 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 DNA damage. Our findings may have therapeutic implications for cytosolic DNA-associated inflammatory diseases.