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

Huai-Chia Chuang; Joung-Liang Lan; Der-Yuan Chen; Chia-Yu Yang; Yi-Ming Chen; Ju-Pi Li; Ching-Yu Huang; Pao-En Liu; Xiaohong Wang; Tse-Hua Tan

doi:10.1038/ni.2121

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.

Authors

Huai-Chia Chuang¹, Joung-Liang Lan, Der-Yuan Chen, Chia-Yu Yang, Yi-Ming Chen, Ju-Pi Li, Ching-Yu Huang, Pao-En Liu, Xiaohong Wang, Tse-Hua Tan

Affiliation

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

PMID: 21983831
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