Unknown

Dataset Information

0

DNA-PKcs kinase activity stabilizes the transcription factor Egr1 in activated immune cells.


ABSTRACT: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is known primarily for its function in DNA double-stranded break repair and non-homologous end joining (NHEJ). However, DNA-PKcs also has a critical yet undefined role in immunity impacting both myeloid and lymphoid cell lineages spurring interest in targeting DNA-PKcs for therapeutic strategies in immune-related diseases. To gain insight into the function of DNA-PKcs within immune cells, we performed a quantitative phosphoproteomic screen in T cells to identify phosphorylation targets of DNA-PKcs. Our results indicate that DNA-PKcs phosphorylates the transcription factor Egr1 (early growth response protein 1) at serine 301. Expression of Egr1 is induced early upon T cell activation and dictates T cell response by modulating expression of cytokines and key costimulatory molecules such as IL (interleukin) 2, IL6, IFNγ,and NFκB.Inhibition of DNA-PKcs by treatment with a DNA-PKcs specific inhibitor NU7441 or shRNA knockdown increased proteasomal degradation of Egr1. Mutation of serine 301 to alanine via CRISPR-Cas9 reduced EGR1 protein expression and decreased Egr1-dependent transcription of IL2 in activated T cells. Our findings identify DNA-PKcs as a critical intermediary link between T cell activation and T cell fate, and a novel phosphosite involved in regulating Egr1 activity.

PROVIDER: S-EPMC8551498 | BioStudies |

REPOSITORIES: biostudies

Similar Datasets

2021-12-21 | PXD026352 | Pride
| S-EPMC6716822 | BioStudies
| S-EPMC4414158 | BioStudies
| S-EPMC3540945 | BioStudies
| S-EPMC5410253 | BioStudies
| S-EPMC4191403 | BioStudies
| S-EPMC5355839 | BioStudies
| S-EPMC3475795 | BioStudies
| S-EPMC8793086 | BioStudies
2019-12-10 | GSE141686 | GEO