| Title: |
DNA-PK interacts with cyclic dinucleotides and inhibits type I interferon responses |
| Authors: |
Vila, Isabelle K.; Messaoud-Nacer, Yasmine; Taffoni, Clara; Jardine, Jane; Eloiflin, Roger J.; Augereau, Adeline; Guha, Soumyabrata; Schussler, Moritz; Le Hars, Pierre; McKellar, Joe; Carvalho, Tamara; Postal, Jeanne; Chemarin, Morgane; Re, Joanna; Guivel-Benhassine, Florence; Lopez, Raphaëlle; Trillet, Kilian; Barrat, Jennifer; Serbier, Maximin; El Mansouri, Insaf; Luchsinger, Charlotte; Chrousos, George P.; Porrot, Françoise; Diaz-Griffero, Felipe; Schwartz, Olivier; Blanchet, Fabien P.; Majzoub, Karim; Bidère, Nicolas; Vlachakis, Dimitrios; Laguette, Nadine |
| Contributors: |
European Research Council; Institut National du Cancer; Ligue pour la recherche contre le cancer; Agence Nationale de Recherches sur le Sida et les Hépatites Virales; University of Montpellier; Fondation ARC; La Région Languedoc Roussillon; Fondation de France; Fondation pour la Recherche Médicale; Centre National de La Recherche Scientifique; Institut Pasteur; Vaccine Research Institute; DURABLE; Health Emergency Preparedness and Response Authority; European Union; Agence Nationale de la Recherche |
| Source: |
Journal of Experimental Medicine ; volume 223, issue 5 ; ISSN 0022-1007 1540-9538 |
| Publisher Information: |
Rockefeller University Press |
| Publication Year: |
2026 |
| Description: |
Inflammatory signal termination is critical for the maintenance of homeostasis. Cyclic dinucleotides (CDNs) are second messengers that trigger inflammatory responses through the activation of the stimulator of IFN 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 2′3′-cGAMP CDN through its kinase domain, tempering STING activation. DNA-PKcs also acts on the 3′3′-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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1084/jem.20251796 |
| DOI: |
10.1084/jem.20251796/2029090/jem_20251796.pdf |
| Availability: |
https://doi.org/10.1084/jem.20251796; https://rupress.org/jem/article-pdf/doi/10.1084/jem.20251796/2029090/jem_20251796.pdf |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.3247E76D |
| Database: |
BASE |