Cytoplasmic‐translocated Ku70 senses intracellular DNA and mediates interferon‐lambda1 induction
| Autor: | Qian Chen, Tomozumi Imamichi, Hongyan Sui |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cytoplasm Immunology Intracellular Space translocation Chromosomal translocation Herpesvirus 1 Human 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Species Specificity Interferon medicine Immunology and Allergy Humans Ku70 Nuclear protein Nuclear export signal Ku Autoantigen IFN‐λ1 Antibiotics Antineoplastic DNA virus Acetylation Herpes Simplex Transfection Original Articles Cell biology Up-Regulation Protein Transport 030104 developmental biology HEK293 Cells chemistry DNA Viral Fatty Acids Unsaturated Original Article Interferons DNA cytosolic DNA sensor 030215 immunology medicine.drug |
| Zdroj: | Immunology |
| ISSN: | 1365-2567 0019-2805 |
| Popis: | Summary We have previously identified that human Ku70, a nuclear protein, serves as a cytosolic DNA sensor. Upon transfection with DNA or infection with DNA virus, Ku70 translocates from the nucleus into the cytoplasm and then predominately induces interferon lambda1 (IFN‐λ1) rather than IFN‐alpha or IFN‐beta, through a STING‐dependent signalling pathway. However, a detailed mechanism for Ku70 cytoplasmic translocation and its correlation with IFN‐λ1 induction have not been fully elucidated. Here, we observed that cytoplasmic translocation of Ku70 only occurred in DNA‐triggered IFN‐λ1‐inducible cells. Additionally, infection by Herpes simplex virus type‐1 (HSV‐1), a DNA virus, induces cytoplasmic translocation of Ku70 and IFN‐λ1 induction in a strain‐dependent manner: the translocation and IFN‐λ1 induction were detected upon infection by HSV‐1 McKrae, but not MacIntyre, strain. A kinetic analysis indicated that cytoplasmic translocation of Ku70 was initiated right after DNA transfection and was peaked at 6 hr after DNA stimulation. Furthermore, treatment with leptomycin B, a nuclear export inhibitor, inhibited both Ku70 translocation and IFN‐λ1 induction, suggesting that Ku70 translocation is an essential and early event for its cytosolic DNA sensing. We further confirmed that enhancing the acetylation status of the cells promotes Ku70’s cytoplasmic accumulation, and therefore increases DNA‐mediated IFN‐λ1 induction. These findings provide insights into the molecular mechanism by which the versatile sensor detects pathogenic DNA in a localization‐dependent manner. Cytoplasmic‐translocated Ku70 recognizes intracellular DNA and initiates downstream STING‐TBK1‐IRFs signalling pathway to induce IFN‐λ1. The translocation of Ku70 from the nucleus to the cytoplasm is an early and required event in Ku70/DNA‐mediated IFN‐λ1 induction. Acetylation plays an essential role in modulating ku70’s cytosolic DNA sensing. |
| Databáze: | OpenAIRE |
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