Cooperative activation of transcription by autoimmune regulator AIRE and CBP
Cooperative activation of transcription by autoimmune regulator AIRE and CBP
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DOI：
10.1016/j.bbrc.2005.05.187
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发表时间：
2005-08-05
影响因子：
3.1
通讯作者：
Peterson, P
中科院分区：
文献类型：
--
作者：
Pitkänen, J;Rebane, A;Peterson, P
自身免疫调节因子(AIRE)是一种转录调节因子，被认为控制胸腺中组织特异性基因的表达。突变的AIRE是遗传性自身免疫性疾病APECED的发病原因。AIRE能够形成核小体(NBS)并与普遍存在的转录共激活因子CBP相互作用。在这篇文章中，我们发现CBP和AIRE协同激活不同启动子报告上的转录，而在APECED患者中发现的AIRE基因突变R257X干扰了这种共激活作用。此外，AIRE和CBP的过表达协同增强了内源性干扰素β的mRNA表达。免疫组织化学研究表明，CBP是AIRE NBS的组成部分，这取决于核蛋白的平衡。我们还表明，AIRE NBS缺乏活性染色质，因此不存在转录位点。此外，我们通过3D分析证明，当共同定位时，AIRE和CBP在AIRE NBS内的空间位置不同。总之，我们的数据表明，AIRE与CBP合作激活了靶基因的转录，即自身抗原，这种激活发生在AIRE NBS之外。(C)2005 Elsevier Inc.保留所有权利。
Autoimmune regulator (AIRE) is a transcriptional regulator that is believed to control the expression of tissue-specific genes in the thymus. Mutated AIRE is responsible for onset of the hereditary autoimmune disease APECED. AIRE is able to form nuclear bodies (NBs) and interacts with the ubiquitous transcriptional coactivator CBP. In this paper, we show that CBP and AIRE synergistically activate transcription on different promoter reporters whereas AIRE gene mutation R257X, found in APECED patients, interferes with this coactivation effect. Furthermore, the overexpression of AIRE and CBP collaboratively enhance endogenous IFN beta mRNA expression. The immunohistochemical studies suggest that CBP, depending on the balance of nuclear proteins, is a component of AIRE NBs. We also show that AIRE NBs are devoid of active chromatin and, therefore, not sites of transcription. In addition, we demonstrate by 3D analyses that AIRE and CBP, when colocalizing, are located spatially differently within AIRE NBs. In conclusion, our data suggest that AIRE activates transcription of the target genes, i.e., autoantigens in collaboration with CBP and that this activation occurs outside of AIRE NBs. (c) 2005 Elsevier Inc. All rights reserved.