Protein kinase C-theta (PKC-theta) is required for activation of the transcription factor NF-kappa B induced by signaling via the T cell antigen receptor (TCR); however, the direct activator of PKC-theta is unknown. We report that the kinase GLK (MAP4K3) directly activated PKC-theta 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-theta 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-theta, and activation of GLK-PKC-theta-IKK could be used as new diagnostic biomarkers and therapeutic targets for systemic lupus erythematosus
