Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: roles of calcineurin binding and cellular location
Identification of the immunophilins capable of mediating inhibition of signal transduction by cyclosporin A and FK506: roles of calcineurin binding and cellular location
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DOI：
10.1128/mcb.13.8.4760-4769.1993
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发表时间：
1993-08
影响因子：
5.3
通讯作者：
Richard J. Bram;Deborah T. Hung;Patrick K. Martin;Stuart L. Schreiber;Gerald R. Crabtree
中科院分区：
文献类型：
--
作者：
Richard J. Bram;Deborah T. Hung;Patrick K. Martin;Stuart L. Schreiber;Gerald R. Crabtree
免疫抑制剂环孢菌素 A (CsA) 和 FK506 似乎通过抑制钙调节磷酸酶钙调神经磷酸酶来阻断 T 细胞功能。虽然这些药物的多种不同的细胞内受体（亲环素和 FKBP，统称为亲免素）已被表征，但功能活性受体尚未被识别。我们发现亲环蛋白 A 或 B 或 FKBP12 的过表达分别增加了 T 细胞对 CsA 或 FK506 的敏感性，证明它们能够在体内介导各自免疫抑制剂的抑制作用。相反，亲环蛋白C、FKBP13和FKBP25则没有效果。体外直接比较每种药物-亲免素复合物对钙调神经磷酸酶的 Ki 值表明，虽然钙调神经磷酸酶的结合显然是必要的，但不足以解释亲免素的体内活性。亚细胞定位也发挥了作用，因为亲环蛋白 B 和 C 的基因删除改变了它们的细胞内位置，从而显着改变了它们的活性。先前已证明亲环蛋白 B 位于含钙细胞内囊泡内；它介导 CsA 抑制的能力意味着信号转导机制的某些组件在细胞内也受到空间限制。
The immunosuppressants cyclosporin A (CsA) and FK506 appear to block T-cell function by inhibiting the calcium-regulated phosphatase calcineurin. While multiple distinct intracellular receptors for these drugs (cyclophilins and FKBPs, collectively immunophilins) have been characterized, the functionally active ones have not been discerned. We found that overexpression of cyclophilin A or B or FKBP12 increased T-cell sensitivity to CsA or FK506, respectively, demonstrating that they are able to mediate the inhibitory effects of their respective immunosuppressants in vivo. In contrast, cyclophilin C, FKBP13, and FKBP25 had no effect. Direct comparison of the Ki of each drug-immunophilin complex for calcineurin in vitro revealed that although calcineurin binding was clearly necessary, it was not sufficient to explain the in vivo activity of the immunophilin. Subcellular localization was shown also to play a role, since gene deletions of cyclophilins B and C which changed their intracellular locations altered their activities significantly. Cyclophilin B has been shown previously to be located within calcium-containing intracellular vesicles; its ability to mediate CsA inhibition implies that certain components of the signal transduction machinery are also spatially restricted within the cell.