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

Nat Immunol. 2011 Oct 9;12(11):1113-8. doi: 10.1038/ni.2121.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Autoimmunity / genetics
  • Disease Progression
  • Female
  • Humans
  • Isoenzymes / genetics
  • Isoenzymes / immunology
  • Isoenzymes / metabolism*
  • Jurkat Cells
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocyte Activation / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • Protein Kinase C / genetics
  • Protein Kinase C / immunology
  • Protein Kinase C / metabolism*
  • Protein Kinase C-theta
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / immunology
  • Protein-Serine-Threonine Kinases / metabolism*
  • RNA, Small Interfering / genetics
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology

Substances

  • Isoenzymes
  • NF-kappa B
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell
  • MAP4K3 protein, human
  • Protein-Serine-Threonine Kinases
  • Prkcq protein, mouse
  • Protein Kinase C
  • Protein Kinase C-theta