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- Title
STING is an essential mediator of the Ku70-mediated production of IFN-λ1 in response to exogenous DNA.
- Authors
Hongyan Sui; Ming Zhou; Hiromi Imamichi; Xiaoli Jiao; Sherman, Brad T.; Lane, H. Clifford; Tomozumi Imamichi
- Abstract
We previously identified Ku70, a subunit of a DNA repair protein complex, as a cytosolic DNA sensor that induces the production of interferon-λ1 (IFN-λ1) by human primary cells and cell lines. IFN-λ1 is a type III IFN and has similar antiviral activity to that of the type I IFNs (IFN-α and IFN-β). We observed that human embryonic kidney (HEK) 293T cells, which are deficient in the innate immune adaptor protein STING (stimulator of IFN genes), did not produce IFN-λ1 in response to DNA unless they were reconstituted with STING. Conversely, parental HEK 293 cells produced IFN-λ1 after they were exposed to exogenous DNA; however, when STING was knocked out in the HEK 293 cells through the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 genome editing system, they lost this response. Through confocal microscopy, we demonstrated that endogenous Ku70 was located in the nucleus and then translocated to the cytoplasmuponDNA exposure to form a complex with STING. Additionally, the DNA binding domain of Ku70 was essential for formation of the Ku70-STING complex. Knocking down STING in primary human macrophages inhibited their ability to produce IFN-λ1 in response to transfection with DNA or infection with the DNA virus HSV-2 (herpes simplex virus-2). Together, these data suggest that STING mediates the Ku70- mediated IFN-λ1 innate immune response to exogenous DNA or DNA virus infection.
- Subjects
DNA repair; GENOME editing; DNA-binding proteins; INTERFERON alpha; PALINDROMIC DNA
- Publication
Science Signaling, 2017, Vol 10, Issue 488, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.aah5054