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

被引:121
作者
Chuang, Huai-Chia [1 ]
Lan, Joung-Liang [2 ,3 ]
Chen, Der-Yuan [2 ,3 ]
Yang, Chia-Yu [1 ]
Chen, Yi-Ming [2 ,3 ]
Li, Ju-Pi [1 ]
Huang, Ching-Yu [1 ]
Liu, Pao-En [2 ]
Wang, Xiaohong [4 ]
Tan, Tse-Hua [1 ,4 ]
机构
[1] Natl Hlth Res Inst, Immunol Res Ctr, Zhunan, Taiwan
[2] Taichung Vet Gen Hosp, Div Allergy Immunol & Rheumatol, Taichung, Taiwan
[3] Natl Yang Ming Univ, Fac Med, Taipei 112, Taiwan
[4] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA
关键词
C-THETA; DIFFERENTIAL REQUIREMENT; DEFICIENT MICE; ENCEPHALOMYELITIS; RECRUITMENT; RECEPTOR; PATHWAY; COMPLEX; CARMA1; DEPEND;
D O I
10.1038/ni.2121
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:1113 / U121
页数:7
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