Cutting Edge: Ku70 Is a Novel Cytosolic DNA Sensor That Induces Type III Rather Than Type I IFN

TLDR

Cytosolic foreign DNA is detected by pattern recognition receptors and mainly induces type I IFN production. The authors used pull‑down assays to show that cytosolic Ku70/Ku80 bind DNA and that nuclear activation of IRF‑1 and IRF‑7 drives IFN‑λ1 transcription via promoter elements in domain I and ISRE sites. The study demonstrates that transfection of DNA into untreated cells preferentially elicits IFN‑λ1, and that Ku70 functions as a novel cytosolic DNA sensor that activates IFN‑λ1 transcription, marking the first evidence of Ku70 mediating type III IFN induction.

Abstract

Abstract Cytosolic foreign DNA is detected by pattern recognition receptors and mainly induces type I IFN production. We found that transfection of different types of DNA into various untreated cells induces type III IFN (IFN-λ1) rather than type I IFN, indicating the presence of uncharacterized DNA sensor(s). A pull-down assay using cytosolic proteins identified that Ku70 and Ku80 are the DNA-binding proteins. The knockdown studies and the reporter assay revealed that Ku70 is a novel DNA sensor inducing the IFN-lambda1 activation. The functional analysis of IFNL1 promoter revealed that positive-regulatory domain I and IFN-stimulated response element sites are predominantly involved in the DNA-mediated IFNL1 activation. A pull-down assay using nuclear proteins demonstrated that the IFN-λ1 induction is associated with the activation of IFN regulatory factor-1 and -7. Thus, to our knowledge, we show for the first time that Ku70 mediates type III IFN induction by DNA.