DNA-PK interacts with cyclic dinucleotides and inhibits type I interferon responses

  • J Exp Med. 2026 May 4;223(5):e20251796. doi: 10.1084/jem.20251796.
Isabelle K Vila  #  1 ,  Yasmine Messaoud-Nacer  #  1 ,  Clara Taffoni  #  1 ,  Jane Jardine  2 ,  Roger J Eloiflin  1 ,  Adeline Augereau  1 ,  Soumyabrata Guha  1 ,  Moritz Schussler  1 ,  Pierre Le Hars  1 ,  Joe McKellar  1 ,  Tamara Carvalho  3 ,  Jeanne Postal  4  5 ,  Morgane Chemarin  1 ,  Joanna Re  1 ,  Florence Guivel-Benhassine  4  5 ,  Raphaëlle Lopez  3 ,  Kilian Trillet  2 ,  Jennifer Barrat  1 ,  Maximin Serbier  1 ,  Insaf El Mansouri  1 ,  Charlotte Luchsinger  6 ,  George P Chrousos  7 ,  Françoise Porrot  4  5 ,  Felipe Diaz-Griffero  6 ,  Olivier Schwartz  4 ,  Fabien P Blanchet  3 ,  Karim Majzoub  1 ,  Nicolas Bidère  2 ,  Dimitrios Vlachakis  7  8  9 ,  Nadine Laguette  1
Affiliations
  • 1. Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier, Centre National de la Recherche Scientifique (CNRS) UMR5535 , Montpellier, France.
  • 2. Team SOAP, CRCI2NA, Nantes Université, Inserm, CNRS, Université d'Angers Nantes France, Equipe Labellisée Ligue Contre le Cancer , Paris, France.
  • 3. Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS UMR9004 , Montpellier, France.
  • 4. Institut Pasteur, Virus and Immunity Unit, Université Paris Cité , Paris, France.
  • 5. Vaccine Research Institute , Créteil, France.
  • 6. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
  • 7. University Research Institute of Maternal and Child Health & Precision Medicine, and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital , Athens, Greece.
  • 8. Laboratory of Genetics, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, Athens, Greece.
  • 9. School of Informatics, Faculty of Natural & Mathematical Sciences, King's College London, London, UK.
  • # Contributed equally.
PMID: 41874365 DOI: 10.1084/jem.20251796
Abstract

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.

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