A study on an immunosuppressant mizoribine-binding renal proteins (esp. molecular chaperones)

1. 哺乳动物HSP60是免疫抑制剂mizoribine的主要靶点（文献1）从猪肾中分离到一个60 kda的mizoribine结合蛋白。根据氨基酸序列鉴定该蛋白为HSP60。此外，米佐利滨干扰了HSP60的伴侣活性。这些发现提示，米佐利滨治疗效果的一种机制可能是抑制HSP60.2的伴侣活性。免疫抑制剂米佐利滨与14-3-3蛋白的功能相互作用（文献2）从猪肾中分离到4个30-32 kDa的米佐利滨结合蛋白。根据它们的氨基酸序列，蛋白质被鉴定为14-3-3蛋白异构体，最近被认为是分子伴侣。米佐利滨影响了1个4-3-3蛋白的构象，增强了糖皮质激素受体(GR)/14-3-3蛋白的相互作用。米佐利滨对GR的转录激活也有刺激作用。这些结果表明，米佐利滨治疗效果的一种机制可能是通过14-3-3蛋白调节GR功能。通过14-3-3依赖性细胞内协同抑制因子RIP140的重定位调控糖皮质激素受体活性（文献3）。在文献2中被鉴定为mizoribinine结合蛋白的14-3-3蛋白的功能被进一步阐明。14-3-3蛋白与核受体共抑制因子RIP140相互作用，改变其亚细胞定位。这些结果表明，14-3-3对糖皮质激素受体转激活的积极作用是由于14-3-3与RIP140结合并从细胞核中去除负作用的RIP140。此外，14-3-3蛋白还能与其他多种核受体和辅因子结合。这表明14-3-3蛋白在信号转导系统中具有更普遍的作用。

1. Mammalian HSP60 is a major target for an immunosuppressant mizoribine (Reference 1)A 60-kDa mizoribine-binding protein was isolated from porcine kidney. Based on its amino acid sequences, the protein was identified as HSP60. Moreover, mizoribine interfered with the chaperone activity of HSP60. These findings suggest the possibility that one mechanism for the therapeutic effect of mizoribine could be to inhibit the chaperone activity of HSP60.2. Functional interaction of the immunosuppressant mizoribine with the 14-3-3 protein (Reference 2)Four 30-32 kDa mizoribine-binding proteins were isolated from porcine kidney. Based on their amino acid sequences, the. proteins were identified as 14-3-3 protein isoforms, which have recently been considered to be molecular chaperones. Mizoribine affected the conformation of 1 4-3-3 proteins and enhanced the glucocorticoid receptor (GR)/14-3-3 protein interaction. Mizoribine also had a stimulatory effect on transcriptional activation by the GR. These results point to the possibility that one mechanism for the therapeutic effect of mizoribine could be to regulate the GR function via 14-3-3 proteins.3. Regulation of glucocorticoid receptor activity by 14-3-3-dependent intracellular relocalization of the corepressor RIP140 (Reference 3)The function of 14-3-3 proteins, which were identified as mizoribine-binding proteins in Reference 2, was further elucidated. 14-3-3 proteins interacted with the nuclear receptor corepressor RIP140 and changed its subcellular localization. These results suggest that the positive effect of 14-3-3 on glucocorticoid receptor transactivation is due to 14-3-3 binding to RIP140 and removing the negatively acting RIP140 from the nucleus. Moreover, 14-3-3 proteins could bind to various other nuclear receptors and co factors. This indicates a more general role for 14-3-3 proteins in the signal transduction systems.