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The kinase GLK controls autoimmunity and NF-κB signaling by activating the kinase PKC-θ in T cells

Nature Immunology volume 12, pages 11131118 (2011) | Download Citation

Abstract

Protein kinase C-θ (PKC-θ) is required for activation of the transcription factor NF-κB induced by signaling via the T cell antigen receptor (TCR); however, the direct activator of PKC-θ is unknown. We report that the kinase GLK (MAP4K3) directly activated PKC-θ during TCR signaling. TCR signaling activated GLK by inducing its direct interaction with the upstream adaptor SLP-76. GLK-deficient mice had impaired immune responses and were resistant to experimental autoimmune encephalomyelitis. Consistent with that, people with systemic lupus erythematosus had considerable enhanced GLK expression and activation of PKC-θ and the kinase IKK in T cells, and the frequency of GLK-overexpressing T cells was directly correlated with disease severity. Thus, GLK is a direct activator of PKC-θ, and activation of GLK–PKC-θ–IKK could be used as new diagnostic biomarkers and therapeutic targets for systemic lupus erythematosus.

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Acknowledgements

We thank the Core Facilities of the National Health Research Institutes (Taiwan) for confocal microscopy. Supported by National Health Research Institutes of Taiwan (98A1-IMPP01-014 to T.-H.T.) and Taichung Veterans General Hospital of Taiwan (TCVGH-NHRI01 to J.-L.L.).

Author information

Author notes

    • Joung-Liang Lan
    • , Der-Yuan Chen
    •  & Chia-Yu Yang

    These authors contributed equally to this work.

Affiliations

  1. Immunology Research Center, National Health Research Institutes, Zhunan, Taiwan.

    • Huai-Chia Chuang
    • , Chia-Yu Yang
    • , Ju-Pi Li
    • , Ching-Yu Huang
    •  & Tse-Hua Tan
  2. Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan.

    • Joung-Liang Lan
    • , Der-Yuan Chen
    • , Yi-Ming Chen
    •  & Pao-En Liu
  3. Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.

    • Joung-Liang Lan
    • , Der-Yuan Chen
    •  & Yi-Ming Chen
  4. Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.

    • Xiaohong Wang
    •  & Tse-Hua Tan

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Contributions

H.-C.C. designed and did experiments, analyzed and interpreted data and wrote the manuscript; J.-L.L. and D.-Y.C. provided samples from affected people, analyzed clinical data and coordinated clinical research; C.-Y.Y., J.-P.L. and P.-E.L. did experiments; Y.-M.C. provided samples from affected people and analyzed clinical data; C.-Y.H. assisted in generation of the GLK-deficient mice; X.W. assisted in the experimental design and manuscript writing; and T.-H.T. conceived of the study, supervised experiments and composed the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tse-Hua Tan.

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DOI

https://doi.org/10.1038/ni.2121

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