NF-κB Transcriptional Activity Is Modulated by FK506-binding Proteins FKBP51 and FKBP52 A ROLE FOR PEPTIDYL-PROLYL ISOMERASE ACTIVITY
NF-κB Transcriptional Activity Is Modulated by FK506-binding Proteins FKBP51 and FKBP52 A ROLE FOR PEPTIDYL-PROLYL ISOMERASE ACTIVITY
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DOI：
10.1074/jbc.m114.582882
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发表时间：
2014-09-19
影响因子：
4.8
通讯作者：
Galigniana, Mario D.
中科院分区：
文献类型：
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作者：
Erlejman, Alejandra G.;De Leo, Sonia A.;Galigniana, Mario D.
Hsp90结合的亲免疫蛋白FKBP51和FKBP52调节类固醇受体运输和激素依赖性生物反应。为了将该模型扩展到其他同样受核细胞质穿梭影响的核因子，我们分析了这些亲免疫蛋白是否调节NF-kappa B信号传导。结果表明，FKBP51会损害NF-kappa B的核易位率及其转录活性。FKBP51的抑制作用既不依赖于亲免疫蛋白的肽基脯氨酸异构酶活性，也不依赖于其与Hsp90的关联。FKBP51的TPR结构域是必不可少的。另一方面，FKBP52有利于RelA的核保留时间、与DNA一致结合序列的关联以及NF-kappa B的转录活性，后者的作用强烈依赖于肽基脯氨酸异构酶活性和FKBP52的TPR结构域，但不需要与Hsp90相互作用。在未受刺激的细胞中，FKBP51与细胞质RelA形成内源性复合物。细胞受到佛波酯刺激后，NF-kappa B可溶性复合物将FKBP51交换为FKBP52，从而触发NF-kappa B的生物效应。重要的是，FKBP52在功能上被募集到NF-kappa B靶基因的启动子区域，而FKBP51则被释放。竞争实验表明两种亲免疫蛋白相互拮抗，纯化蛋白结合实验表明RelA和亲免疫蛋白可能直接相关。这些观察结果表明，NF-kappa B在不同细胞类型中的生物学作用可能受到高FKBP52/FKBP51表达比的正向调节，其有利于NF-kappa B的核保留、靶基因启动子区域的招募和转录活性。
Hsp90 binding immunophilins FKBP51 and FKBP52 modulate steroid receptor trafficking and hormone-dependent biological responses. With the purpose to expand this model to other nuclear factors that are also subject to nuclear-cytoplasmic shuttling, we analyzed whether these immunophilins modulate NF-kappa B signaling. It is demonstrated that FKBP51 impairs both the nuclear translocation rate of NF-kappa B and its transcriptional activity. The inhibitory action of FKBP51 requires neither the peptidylprolyl-isomerase activity of the immunophilin nor its association with Hsp90. The TPR domain of FKBP51 is essential. On the other hand, FKBP52 favors the nuclear retention time of RelA, its association to a DNA consensus binding sequence, and NF-kappa B transcriptional activity, the latter effect being strongly dependent on the peptidylprolyl-isomerase activity and also on the TPR domain of FKBP52, but its interaction with Hsp90 is not required. In unstimulated cells, FKBP51 forms endogenous complexes with cytoplasmic RelA. Upon cell stimulation with phorbol ester, the NF-kappa B soluble complex exchanges FKBP51 for FKBP52, and the NF-kappa B biological effect is triggered. Importantly, FKBP52 is functionally recruited to the promoter region of NF-kappa B target genes, whereas FKBP51 is released. Competition assays demonstrated that both immunophilins antagonize one another, and binding assays with purified proteins suggest that the association of RelA and immunophilins could be direct. These observations suggest that the biological action of NF-kappa B in different cell types could be positively regulated by a high FKBP52/FKBP51 expression ratio by favoring NF-kappa B nuclear retention, recruitment to the promoter regions of target genes, and transcriptional activity.