Cytosolic branched chain aminotransferase (BCATc) regulates mTORC1 signaling and glycolytic metabolism in CD4+ T cells.
Here we show that expression of the cytosolic branched chain aminotransferase (BCATc) is triggered by the T cell receptor (TCR) of CD4(+) T cells. Induction of BCATc correlates with increased Leu transamination, whereas T cells from the BCATc(-/-) mouse exhibit lower Leu transamination and higher intracellular Leu concentrations than the cells from wild type (WT) mice. Induction of BCATc by TCR in WT cells is prevented by the calcineurin-nuclear factor of activated T cells (NFAT) inhibitor, cyclosporin A (CsA), suggesting that NFAT controls BCATc expression. Leu is a known activator of the mammalian target of rapamycin complex 1 (mTORC1). mTOR is emerging as a critical regulator of T cell activation, differentiation, and metabolism. Activated T cells from BCATc(-/-) mice show increased phosphorylation of mTORC1 downstream targets, S6 and 4EBP-1, indicating higher mTORC1 activation than in T cells from WT mice. Furthermore, T cells from BCATc(-/-) mice display higher rates of glycolysis, glycolytic capacity, and glycolytic reserve when compared with activated WT cells. These findings reveal BCATc as a novel regulator of T cell activation and metabolism and highlight the important role of Leu metabolism in T cells.
From the Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, Virginia 24061 and eanani75@vt.edu.
Elitsa A
EA
Ananieva
the Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Chirag H
CH
Patel
the Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Charles H
CH
Drake
the Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Jonathan D
JD
Powell
From the Department of Human Nutrition, Foods and Exercise, Virginia Tech, Blacksburg, Virginia 24061 and.
Susan M
SM
Hutson
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006019:Glycolysis; D007930:Leucine / Q000378:metabolism; D008213:Lymphocyte Activation; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000637:Transaminases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D046912:Multiprotein Complexes; D011948:Receptors, Antigen, T-Cell; D000637:Transaminases; C019798:branched-chain-amino-acid transaminase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D007930:Leucine
Amino Acid; Amino Acid Transport; BCATc; CD4+ T Cells; Glycolysis; Leu; Lymphocyte; Mammalian Target of Rapamycin (mTOR); T Cell Anergy