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Updated: Mar 25, 2026
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Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle
Published on: March 5, 2019
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DNA-PK interacts with cyclic dinucleotides and inhibits type I interferon responses
Isabelle K Vila1, Yasmine Messaoud-Nacer1, Clara Taffoni1
1Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier, Centre National de la Recherche Scientifique (CNRS) UMR5535 , Montpellier, France.
The Journal of Experimental Medicine
|March 24, 2026
Summary
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) regulates inflammatory signals by interacting with cyclic dinucleotides (CDNs), tempering STING activation. This discovery offers new insights into CDN regulation and STING-targeting therapeutics.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- Inflammatory signal termination is crucial for maintaining bodily homeostasis.
- Cyclic dinucleotides (CDNs) act as second messengers, activating the stimulator of IFN genes (STING) signaling pathway and initiating inflammatory responses.
- Currently, no broad-acting direct regulator of intracellular CDNs has been identified in mammals.
Purpose of the Study:
- To identify and characterize a direct regulator of intracellular cyclic dinucleotides (CDNs) in mammals.
- To investigate the interaction between DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and CDNs.
- To explore the implications of this interaction for STING signaling and potential therapeutic development.
Main Methods:
- Biochemical assays to demonstrate direct interaction between DNA-PKcs and 2'3'-cGAMP.
- Enzyme kinetics studies to assess the effect of CDNs on DNA-PKcs kinase activity.
- Functional assays to evaluate the impact of DNA-PKcs on STING activation and antiviral responses.
Main Results:
- DNA-dependent protein kinase catalytic subunit (DNA-PKcs) directly binds to the intracellular 2'3'-cGAMP CDN via its kinase domain.
- DNA-PKcs modulates the bioactivity of both intracellular (2'3'-cGAMP) and bacterial (3'3'-cGAMP) CDNs, as well as pharmacological STING agonists.
- CDNs were found to inhibit the kinase activity of DNA-PKcs.
Conclusions:
- DNA-PKcs acts as a direct regulator of intracellular CDN signaling, tempering STING activation.
- The interplay between DNA-PKcs and CDNs provides critical insights into the regulation of inflammatory pathways.
- This research has significant implications for the development of novel STING-targeting therapeutics for human pathologies involving immunosuppression.
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