Summary
Cytosolic dsDNAs are potent immune-stimulatory molecules that trigger inflammation in several human pathologies 1,2. A major pathway for the detection of cytosolic dsDNA relies on the cyclic GMP-AMP (cGAMP) synthase (cGAS) that produces the 2’3’-cGAMP cyclic dinucleotide (CDN) for activation of the Stimulator of Interferon Genes (STING) adaptor protein that subsequently drives type I Interferon (IFN) responses 3,4. Here, we investigated the mechanism regulating intracellular 2’3’-cGAMP levels. We show that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a major player in the repair of double-strand breaks, directly regulates intracellular levels of 2’3’-cGAMP, thereby reducing STING activation. We describe that the binding of 2’3’-cGAMP to DNA-PKcs occurs in its catalytic cleft, impeding its kinase function. Contrary to other CDN regulatory mechanisms that have been shown to primarily regulate extracellular 2’3’-cGAMP, we show that DNA-PKcs also interacts with the 3’3’-cGAMP bacterial CDN, limiting its capacity to activate STING signaling. Furthermore, we found that DNA-PKcs decreases the potency of pharmacological STING activators. As STING is a major target for therapeutic interventions aiming to boost inflammatory responses in immunosuppressed contexts 5, our data bear important implications for drug development and deepens our understanding of inflammatory regulation in response to CDNs.
Competing Interest Statement
The authors have declared no competing interest.