DNA-PKcs, but not TLR9, is required for activation of Akt by CpG-DNA.
CpG-DNA and its related synthetic CpG oligodeoxynucleotides (CpG-ODNs) play an important role in immune cell survival. It has been suggested that Akt is one of the CpG-DNA-responsive serine/threonine kinases; however, the target protein of CpG-DNA that leads to Akt activation has not been elucidated. Here, we report that ex vivo ... stimulation of bone marrow-derived macrophages (BMDMs) from mice lacking the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) results in defective phosphorylation and activation of Akt by CpG-DNA. Unexpectedly, loss of the Toll-like receptor 9 has a minimal effect on Akt activation in response to CpG-DNA. Further in vitro analysis using purified DNA-PK and recombinant Akt proteins reveals that DNA-PK directly induces phosphorylation and activation of Akt. In addition, in BMDMs, DNA-PKcs associates with Akt upon CpG-DNA stimulation and triggers transient nuclear translocation of Akt. Thus, our findings establish a novel role for DNA-PKcs in CpG-DNA signaling and define a CpG-DNA/DNA-PKcs/Akt pathway.
Mesh Terms:
Active Transport, Cell Nucleus, Animals, Bone Marrow, Cells, Cultured, DNA-Activated Protein Kinase, DNA-Binding Proteins, Enzyme Activation, Macrophages, Mice, Mice, Knockout, Oligodeoxyribonucleotides, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Receptors, Cell Surface, Toll-Like Receptor 9
Active Transport, Cell Nucleus, Animals, Bone Marrow, Cells, Cultured, DNA-Activated Protein Kinase, DNA-Binding Proteins, Enzyme Activation, Macrophages, Mice, Mice, Knockout, Oligodeoxyribonucleotides, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Receptors, Cell Surface, Toll-Like Receptor 9
EMBO J.
Date: Feb. 23, 2005
PubMed ID: 15678105
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