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

## TL;DR

This study reveals that DNA-PKcs interacts with cyclic dinucleotides, regulating their signaling and inhibiting interferon responses.

## Contribution

DNA-PKcs is identified as a novel regulator of CDN signaling and is shown to be inhibited by CDNs.

## Key findings

- DNA-PKcs interacts with 2′3′-cGAMP and 3′3′-cGAMP to temper STING activation.
- CDNs inhibit DNA-PKcs kinase activity, affecting antiviral responses.
- DNA-PKcs impacts the bioactivity of STING agonists.

## Abstract

CDN are second messengers that trigger type I IFN responses. Vila et al. show that DNA-PKcs, a major DNA damage response actor, directly interacts with CDNs through its kinase domain, ensuring CDN-associated signal termination, while CDNs inhibit DNA-PKcs catalytic activity.

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.