Role of cyclophilin B in activation of interferon regulatory factor-3
Role of cyclophilin B in activation of interferon regulatory factor-3
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DOI：
10.1074/jbc.m501684200
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发表时间：
2005-05-06
影响因子：
4.8
通讯作者：
Matsuyama, T
中科院分区：
文献类型：
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作者：
Obata, Y;Yamamoto, K;Matsuyama, T
IRF-3是干扰素调节因子（IRF）的成员，并且在病毒感染诱导干扰素-β（IFN-β）中起主要作用。病毒感染导致IRF-3被I κ B激酶α和TANK结合激酶1磷酸化，导致其二聚化并与共激活因子CREB结合蛋白/p300结合。IRF-3全复合物易位到细胞核，在那里它诱导IFN-β。在本研究中，我们研究了IRF-3激活的分子机制。使用细菌双杂交筛选，我们分离出与IRF-3相互作用的分子。其中之一是亲环素B，它是具有顺-反肽基脯氨酰异构酶活性的亲免素的成员。GST下拉试验表明，结合需要IRF-3的自抑制结构域之一和亲环素B的肽基脯氨酰异构酶结构域。通过RNA干扰敲低亲环蛋白B表达导致抑制病毒诱导的IRF-3磷酸化，从而抑制随后的二聚化、与CREB结合蛋白的结合、与靶DNA元件的结合以及IFN-β的诱导。这些发现表明亲环素B在IRF-3活化中起关键作用。
IRF-3 is a member of the interferon regulatory factors (IRFs) and plays a principal role in the induction of interferon-beta (IFN-beta) by virus infection. Virus infection results in the phosphorylation of IRF-3 by I kappa B kinase epsilon and TANK-binding kinase 1, leading to its dimerization and association with the coactivators CREB-binding protein/p300. The IRF-3 holocomplex translocates to the nucleus, where it induces IFN-beta. In the present study, we examined the molecular mechanism of IRF-3 activation. Using bacterial two-hybrid screening, we isolated molecules that interact with IRF-3. One of these was cyclophilin B, a member of the immunophilins with a cis-trans peptidyl-prolyl isomerase activity. A GST pull-down assay suggested that one of the autoinhibition domains of IRF-3 and the peptidyl-prolyl isomerase domain of cyclophilin B are required for the binding. A knockdown of cyclophilin B expression by RNA interference resulted in the suppression of virus-induced IRF-3 phosphorylation, leading to the inhibition of the subsequent dimerization, association with CREB-binding protein, binding to the target DNA element, and induction of IFN-beta. These findings indicate that cyclophilin B plays a critical role in IRF-3 activation.