RT Journal Article
SR Electronic
T1 DNA-PKcs kinase activity stabilizes the transcription factor Egr1 in activated immune cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.04.446996
DO 10.1101/2021.06.04.446996
A1 Zachary J Waldrip
A1 Lyle Burdine
A1 David K Harrison
A1 Ana Clara Azevedo-Pouly
A1 Aaron J. Storey
A1 Olivia G. Moffett
A1 Samuel G. Mackintosh
A1 Marie Schluterman Burdine
YR 2021
UL http://biorxiv.org/content/early/2021/06/04/2021.06.04.446996.abstract
AB 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 first order phosphorylation targets of DNA-PKcs. Results indicate that DNA-PKcs phosphorylates the transcription factor Egr1 (early growth response protein 1) at S301. Expression of Egr1 is induced early upon T cell activation and dictates T cell response by modulating expression of cytokines and key costimulatory molecules. Mutation of serine 301 to alanine via CRISPR-Cas9 resulted in increased proteasomal degradation of Egr1 and a decrease in Egr1-dependent transcription of IL2 (interleukin-2) 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.Competing Interest StatementThe authors have declared no competing interest.