Brasilicardin A, a natural immunosuppressant, targets amino Acid transport system L.
Lymphocytes in T cell activation require extracellular nutrients to provide energy for cellular proliferation and effector functions. Therefore, inhibitors of nutrient transporters are expected to be a new class of immunosuppressant. Here, we report that the molecular target of brasilicardin A (BraA), an immunosuppressive compound, is the amino acid transporter system L. BraA inhibited the cell-cycle progression of murine T cell lymphocyte CTLL-2 cells in G1 phase, and potently inhibited the uptake of amino acids that are substrates for amino acid transport system L. Moreover, BraA stimulated the GCN2 activation and, subsequently, the phosphorylation of eIF2alpha. These results suggest that the immunosuppressive activity of BraA is induced by amino acid deprivation via the inhibition of system L and that the amino acid transporter is a target for immunosuppressant.
Usui
Takeo
T
Antibiotics Laboratory, Discovery Research Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. usui@riken.jp
Nagumo
Yoko
Y
Watanabe
Ai
A
Kubota
Takaaki
T
Komatsu
Kazusei
K
Kobayashi
Jun'ichi
J
Osada
Hiroyuki
H
D027062:Amino Acid Transport System L / Q000037:antagonists & inhibitors*; D000596:Amino Acids / Q000378:metabolism; D000617:Aminoglycosides / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice
D027062:Amino Acid Transport System L; D000596:Amino Acids; D000617:Aminoglycosides; D007166:Immunosuppressive Agents; C118259:brasilicardin A