Phosphorylation-induced dimerization of interferon regulatory factor 7 unmasks DNA binding and a bipartite transactivation domain
Phosphorylation-induced dimerization of interferon regulatory factor 7 unmasks DNA binding and a bipartite transactivation domain
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DOI：
10.1128/mcb.20.23.8803-8814.2000
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发表时间：
2000-12-01
影响因子：
5.3
通讯作者：
Levy, DE
中科院分区：
文献类型：
--
作者：
Marié, I;Smith, E;Levy, DE
干扰素调节因子7（IRF 7）是一种干扰素（IPN）诱导型转录因子，用于激活病毒感染后以延迟动力学表达的IFN-α基因亚组。IRF 7作为潜伏蛋白合成，并在感染细胞中通过蛋白磷酸化进行后期修饰。磷酸化需要一个羧基末端调节结构域，该结构域控制活性蛋白仅保留在细胞核中，以及其与特定DNA靶序列的结合、多聚化和诱导靶基因表达的能力。IRF 7的转录激活映射到两个不同的区域，这两个区域都是完全活性所需的，而所有功能都被隐藏在潜伏的IRF 7中的自抑制结构域映射到内部区域。通过将IRF 7与雌激素受体（ER）的配体结合和二聚化结构域融合，构建了IRF 7的条件活性形式。嵌合IRF 7-ER的激素依赖性二聚化刺激内源性靶基因的DNA结合和转录反式激活。这些研究表明，IRF 7活性通过磷酸化依赖性变构变化来调节，从而导致二聚化并促进核保留、抑制反式激活并允许特异性DNA结合。
Interferon regulatory factor 7 (IRF7) is an interferon (IPN)-inducible transcription factor required for activation of a subset of IFN-alpha genes that are expressed with delayed kinetics following viral infection. IRF7 is synthesized as a latent protein and is posttranslationally modified by protein phosphorylation in infected cells. Phosphorylation required a carboxyl-terminal regulatory domain that controlled the retention of the active protein exclusively in the nucleus, as well as its binding to specific DNA target sequences, multimerization, and ability to induce target gene expression. Transcriptional activation by IRF7 mapped to two distinct regions, both of which were required for full activity, while all functions were masked in latent IRF7 by an autoinhibitory domain mapping to an internal region. A conditionally active form of IRF7 was constructed by fusing IRF7 with the ligand-binding and dimerization domain of estrogen receptor (ER). Hormone-dependent dimerization of chimeric IRF7-ER stimulated DNA binding and transcriptional transactivation of endogenous target genes. These studies demonstrate the regulation of IRF7 activity by phosphorylation-dependent allosteric changes that result in dimerization and that facilitate nuclear retention, derepress transactivation, and allow specific DNA binding.