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

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.

Automated summary

A class of small cytosolic dsDNA molecules, around 20-40 bp in length, have been found to compete with long dsDNA for binding to cGAS, inhibiting cGAS activation and inflammation. These small DNA molecules promote the interaction between cGAS and Beclin-1, releasing Rubicon, which negatively regulates PI3KC3, from the Beclin-1-PI3KC3 complex. This leads to PI3KC3 activation, inducing autophagy and degradation of STING and long dsDNA. The discovery has therapeutic implications for cytosolic DNA-associated inflammatory diseases.