Isabelle K. Vila, Yasmine Messaoud-Nacer, Clara Taffoni, Jane Jardine, Roger J. Eloiflin, Adeline Augereau, Soumyabrata Guha, Moritz Schussler, Pierre Le Hars, Joe McKellar, Tamara Carvalho, Jeanne Postal, Morgane Chemarin, Joanna Re, Florence Guivel-Benhassine, Raphaëlle Lopez, Kilian Trillet, Jennifer Barrat, Maximin Serbier, Insaf El Mansouri, Charlotte Luchsinger, George P. Chrousos, Françoise Porrot, Felipe Diaz-Griffero, Olivier Schwartz, Fabien P. Blanchet, Karim Majzoub, Nicolas Bidère, Dimitrios Vlachakis, Nadine Laguette

Inflammatory signal termination is critical for the maintenance of homeostasis. Cyclic dinucleotides (CDN) are second messengers that trigger inflammatory responses through the activation of the Stimulator of Interferon Genes (STING) signaling platform. No broad-acting direct regulator of intracellular CDNs has been identified in mammals to date. We show that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a major DNA damage response actor, directly interacts with the intracellular 23-cGAMP CDN through its kinase domain, tempering STING activation. DNA-PKcs also acts on the 33-cGAMP bacterial CDN and pharmacological STING agonists, impacting their bioactivity and ability to mount optimal antiviral responses. STING agonism has been considered as a therapeutic avenue to alleviate immunosuppression in human pathologies. By uncovering DNA-PKcs as a CDN signaling modulator and CDNs as inhibitors of DNA-PKcs kinase activity, we provide critical insights into CDN regulation, with implications for the development of STING-targeting therapeutics.