Gamma-aminobutyric acid transporter 1 negatively regulates T cell activation and survival through protein kinase C-dependent signaling pathways.
Gamma-aminobutyric acid transporter 1 (GAT-1), as the major regulator in maintaining a gamma-aminobutyric acid reservoir in the CNS, plays negative roles in experimental autoimmune encephalomyelitis pathogenesis. Our previous study has revealed that, besides its wide expression in the CNS, GAT-1 expression can be induced on activated T cells triggered by Ag. However, the function of GAT-1 in T cell activation is unclear. In this study, we show that GAT-1 deficiency induces more vigorous cell cycle entry and less cell apoptosis in T cells, thus leading to enhanced cell proliferation. GAT-1 deficiency promotes T cell division and survival by down-regulating cyclin dependent kinase inhibitor p27(kip1), differentially regulating the pro- and anti-apoptotic proteins Bcl-2, Bcl-xl, and Bad and activating transcription factor NF-kappaB through induction of translocation and phosphorylation of protein kinase C (PKC) theta. In addition, our data reveal that GAT-1 expression on T cells is modulated by PKC activation. Taken together, the data show that GAT-1 negatively regulates T cell activation and survival through PKC-dependent signaling pathways.
Wang
Ying
Y
Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Luo
Qingqiong
Q
Xu
Yan
Y
Feng
Dechun
D
Fei
Jian
J
Cheng
Qi
Q
Xu
Lingyun
L
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D050485:GABA Plasma Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*
D050485:GABA Plasma Membrane Transport Proteins; C493414:Slc6a1 protein, mouse; D011493:Protein Kinase C