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

Waldrip, Zachary J; Burdine, Lyle; Harrison, David K.; Azevedo-Pouly, Ana Clara P.; Storey, Aaron J.; Moffett, Olivia G.; Mackintosh, Samuel G.; Burdine, Marie Schluterman

doi:10.1016/j.jbc.2021.101209

Cited by 13 publications

(16 citation statements)

References 34 publications

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“…DNA-PKcs phosphorylates the serine/threonine kinase AKT at serine 473 resulting in kinase activation. 23,27 AKT is phosphorylated in T cells following stimulation. This is required for downstream signaling which promotes the shift to aerobic glycolysis to support increased proliferation and gene transcription in activated T cells.…”

Section: Resultsmentioning

confidence: 99%

“…In our previous studies, we determined DNA-PKcs is required for the activity of the transcription factors NFAT, NF κ B and EGR1 and production of cytokines critical to T cell function, including IL2, IL6, IFN γ , and TNFα. 21–23 Moreover, we showed that treatment with the DNA-PKcs inhibitor NU7441 extended the survival of transplanted allogenic skin grafts in a murine mouse model by reducing T cell-graft infiltration and inflammatory cytokine production. 22 These studies highlight the immunosuppressive effects of DNA-PKcs inhibitors and suggest the potential repurposing of DNA-PKcs inhibitors for immunosuppression therapy for T cell-mediated autoimmune and immune-related diseases and allogenic graft rejection.…”

Section: Introductionmentioning

confidence: 95%

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Inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4⁺ helper and CD8⁺ effector T cells

Azevedo-Pouly

Appell

Burdine

et al. 2022

Preprint

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Modulation of T cell activity is an effective strategy for the treatment of autoimmune diseases, immune-related disorders and cancer. This highlights a critical need for continued investigation of proteins that regulate T cell function. The kinase DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is emerging as a potent regulator of the immune system spurring interest in its use as a therapeutic target for immune-related diseases. In murine models of autoimmune disease including asthma and rheumatoid arthritis, treatment with small molecule DNA-PKcs inhibitors, which are in clinical trials for cancer therapy, decreased disease severity. Additionally, DNA-PKcs inhibitors reduced T cell-mediated graft rejection and extended graft survival in a murine allogenic skin graft rejection model. These in vivo studies suggest the therapeutic use of DNA-PKcs inhibitors for autoimmune and T cell-mediated disorders. In this study, we sought to further characterize the effects of DNA-PKcs inhibitors on T cells to better understand their clinical potential. We determined that pharmacological inhibition of DNA-PKcs abrogated activation of murine and human CD4+ and CD8+ T cells as evident by reduced expression of the activation markers CD69 and CD25. Furthermore, inhibition of DNA-PKcs impeded metabolic pathways and proliferation of anti-CD3/CD28 activated CD4+ and CD8+ T cells as well as peptide-stimulated OTI-CD8+ T cells. This reduced the ability of OTI-CD8+ T cells to kill cancer cells and the expression of IFNγ and the cytotoxic genes eomes, perforin and granzyme B. These results suggest a novel role for DNA-PKcs in early T cell activation. Furthermore, our data support the therapeutic potential of DNA-PKcs inhibitors on diseases of immune dysregulation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4⁺ helper and CD8⁺ effector T cells

Azevedo-Pouly

Appell

Burdine

et al. 2022

Preprint

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“…EGR1 was an immune response related transcription factor ( 62 ). EGR1 could induce T cell activation and response ( 63 ). EGR1 was also a signaling intermediate in B-cell antigen receptor stimulated B cell functional response ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

The combination of SMRT sequencing and Illumina sequencing highlights organ-specific and age-specific expression patterns of miRNAs in Sika Deer

Jia

Wang

et al. 2022

Front. Vet. Sci.

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Due to the lack of high-quality Sika Deer (Cervus nippon) transcriptome and sRNAome across multiple organs or development stages, it is impossible to comprehensively analyze the mRNA and miRNA regulatory networks related to growth, development and immunity response. In this study, we used single molecule-real time sequencing (SMRT-seq) and Illumina sequencing methods to generate transcriptome and sRNAome from ten tissues and four age groups of Sika Deer to help us understand molecular characteristics and global miRNA expression profiles. The results showed that a total of 240,846 consensus transcripts were generated with an average length of 2,784 bp. 4,329 Transcription factors (TFs), 109,000 Simple Sequence Repeats (SSRs) and 18,987 Long non-coding RNAs (LncRNAs) were identified. Meanwhile, 306 known miRNAs and 143 novel miRNAs were obtained. A large number of miRNAs showed organ-specific and age-specific differential expression patterns. In particular, we found that the organ-specific miRNAs were enriched in the brain, some of which shared only between the brain and adrenal. These miRNAs were involved in maintaining specific functions within the brain and adrenal. By constructing miRNA96mRNA interaction networks associated with Sika Deer immunity, we found that miRNAs (miR-148a, miR-26a, miR-214, let-7b, etc.) and mRNAs (CD6, TRIM38, C3, CD163, etc.) might play an important role in the immune response of Sika Deer spleen. Together, our study generated an improved transcript annotation for Sika Deer by SMRT-seq and revealed the role of miRNA in regulating the growth, development and immunity response of Sika Deer.

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“…We determined that DNA-PKcs is required for the activity of the transcription factors NFAT, NFκB and EGR1 and the production of the cytokines IL2, IL6, IFNγ and TNFα. [16][17][18] Moreover, we showed that treatment with the DNA-PKcs inhibitor NU7441 extended the survival of transplanted murine allogenic skin grafts by reducing T cell-graft infiltration and inflammatory cytokine production. 17 These studies highlight the immunosuppressive effects of DNA-PKcs inhibitors in vivo.…”

Section: Introductionmentioning

confidence: 92%

Chemical inhibition of DNA‐PKcs impairs the activation and cytotoxicity of CD4⁺ helper and CD8⁺ effector T cells

et al. 2023

Self Cite

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Modulation of T cell activity is an effective strategy for the treatment of autoimmune diseases, immune-related disorders and cancer. This highlights a critical need for the identification of proteins that regulate T cell function. The kinase DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is emerging as a potent regulator of the immune system, spurring interest in its use as a therapeutic target. In murine models of immune-related diseases including asthma and rheumatoid arthritis, treatment with small-molecule DNA-PKcs inhibitors decreased the disease severity. Additionally, DNA-PKcs inhibitors reduced T cell-mediated graft rejection in a murine allogenic skin graft model. These in vivo studies suggest the use of DNA-PKcs inhibitors as immunotherapy for autoimmune and T cell-mediated disorders. In this study, we sought to characterize further the effects of DNA-PKcs inhibitors on T cells to better understand their clinical potential. We determined that inhibition of DNA-PKcs using inhibitor NU7441 and the inhibitors currently in clinical trials for cancer therapy, M3184 and AZD7648, abrogated the activation of murine and human CD4 + and CD8 + T cells as evidenced by the reduced expression of the activation markers CD69 and CD25. Furthermore, inhibition of DNA-PKcs impeded metabolic pathways and the proliferation of activated T cells. This reduced the ability of OTI-CD8 + T cells to kill cancer cells and the expression of IFNγ and cytotoxic genes. These results highlight a critical role for DNA-PKcs in T cells and validate future studies using DNA-PKcs inhibitors as immune modulation therapy for the treatment of immune-related diseases.

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

Cited by 13 publications

References 34 publications

Inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4⁺ helper and CD8⁺ effector T cells

Inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4⁺ helper and CD8⁺ effector T cells

The combination of SMRT sequencing and Illumina sequencing highlights organ-specific and age-specific expression patterns of miRNAs in Sika Deer

Chemical inhibition of DNA‐PKcs impairs the activation and cytotoxicity of CD4⁺ helper and CD8⁺ effector T cells

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

Cited by 13 publications

References 34 publications

Inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4+ helper and CD8+ effector T cells

Inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4+ helper and CD8+ effector T cells

The combination of SMRT sequencing and Illumina sequencing highlights organ-specific and age-specific expression patterns of miRNAs in Sika Deer

Chemical inhibition of DNA‐PKcs impairs the activation and cytotoxicity of CD4+ helper and CD8+ effector T cells

Contact Info

Product

Resources

About

Inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4⁺ helper and CD8⁺ effector T cells

Inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4⁺ helper and CD8⁺ effector T cells

Chemical inhibition of DNA‐PKcs impairs the activation and cytotoxicity of CD4⁺ helper and CD8⁺ effector T cells