Brasilicardin A, a natural immunosuppressant, targets amino acid transport system L
Brasilicardin A, a natural immunosuppressant, targets amino acid transport system L
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DOI：
10.1016/j.chembiol.2006.09.006
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发表时间：
2006-11-01
影响因子：
--
通讯作者：
Osada, Hiroyuki
中科院分区：
文献类型：
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作者：
Usui, Takeo;Nagumo, Yoko;Osada, Hiroyuki
T细胞活化过程中的淋巴细胞需要细胞外营养物质为细胞增殖和效应器功能提供能量。因此，营养转运蛋白抑制剂有望成为一类新型的免疫抑制剂。在此，我们报道了免疫抑制化合物Brasilardin A(Brasilardin A，BRAA)的分子靶点是氨基酸转运蛋白系统L。BRAA能抑制小鼠T淋巴细胞CTLL-2细胞处于G1期的细胞周期进程，并有效地抑制作为氨基酸转运蛋白L底物的氨基酸的摄取。此外，BRAA还能刺激GCN2的激活，进而促进eIF2α的磷酸化。这些结果表明，BRAA的免疫抑制作用是通过抑制L系统而引起的氨基酸剥夺所致，氨基酸转运体是免疫抑制的靶点。
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 eIF2 alpha. 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.