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  • The EMBO Journal (2005) 24, 779 - 789
  • doi:10.1038/sj.emboj.7600539

Published online: 27 January 2005

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

Ana-Maria Dragoi1, Xiaoying Fu1,a, Stanimir Ivanov1,a, Ping Zhang1, Linbo Sheng2, Dianqing Wu3, Gloria C Li2 and Wen-Ming Chu1

  1. Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
  2. Departments of Radiation Oncology and Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
  3. Departments of Genetics and Development Biology, University of Connecticut, Health Center, Farmington, CT, USA

Correspondence to:

Wen-Ming Chu, Department of Molecular Microbiology and Immunology, Brown University, Box G-B6, Providence, RI 02912, USA. Tel.: +1 401 863 9786; Fax: +1 401 863 1971; E-mail: wen-ming_chu@brown.edu

aThese authors contributed equally to this work

Received 2 June 2004; Accepted 2 December 2004

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.

  • Keywords:

    • Akt,
    • CpG-DNA,
    • DNA-PKcs,
    • TLR9