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DNA-PKcs, but not TLR9, is required for activation of Akt by CpG-DNA

Ana-Maria Dragoi1, Xiaoying Fu, Stanimir Ivanov

  • 1Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.

The EMBO Journal
|January 29, 2005
PubMed

Insights

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) directly activates Akt in response to CpG-DNA, revealing a novel signaling pathway crucial for immune cell survival. Toll-like receptor 9 plays a minimal role.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • CpG-DNA and CpG oligodeoxynucleotides (CpG-ODNs) are vital for immune cell survival.
  • The serine/threonine kinase Akt is implicated in CpG-DNA responses, but its upstream activator remains unknown.

Purpose of the Study:

  • To identify the specific protein target of CpG-DNA that mediates Akt activation.
  • To elucidate the signaling pathway linking CpG-DNA to Akt activation.

Main Methods:

  • Ex vivo stimulation of bone marrow-derived macrophages (BMDMs) from wild-type and DNA-PKcs-deficient mice.
  • In vitro kinase assays using purified DNA-PK and Akt proteins.
  • Analysis of Akt phosphorylation, activation, and subcellular localization upon CpG-DNA stimulation.

Main Results:

  • CpG-DNA failed to activate Akt in BMDMs lacking DNA-PKcs.
  • Toll-like receptor 9 deficiency had minimal impact on Akt activation by CpG-DNA.
  • Purified DNA-PK directly phosphorylated and activated Akt in vitro.
  • DNA-PKcs associated with Akt and induced its nuclear translocation in CpG-DNA-stimulated BMDMs.

Conclusions:

  • DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key mediator of Akt activation by CpG-DNA.
  • A novel signaling pathway, CpG-DNA/DNA-PKcs/Akt, is established.
  • This pathway highlights a new role for DNA-PKcs in innate immune responses.

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