IFN-stimulated gene 15 is synergistically activated through interactions between the myelocyte/lymphocyte-specific transcription factors, PU.1, IFN regulatory factor-8/IFN consensus sequence binding protein, and IFN regulatory factor-4: Characterization of a new subtype of IFN-stimulated response element
IFN-stimulated gene 15 is synergistically activated through interactions between the myelocyte/lymphocyte-specific transcription factors, PU.1, IFN regulatory factor-8/IFN consensus sequence binding protein, and IFN regulatory factor-4: Characterization of a new subtype of IFN-stimulated response element
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DOI：
10.4049/jimmunol.168.12.6224
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发表时间：
2002-06-15
影响因子：
4.4
通讯作者：
Levi, BZ
中科院分区：
文献类型：
--
作者：
Meraro, D;Gleit-Kielmanowicz, M;Levi, BZ
I 型 IFN 引起称为 IFN 刺激基因 (ISG) 的基因子集的诱导，其中含有特定的 DNA 元件，即 IFN 刺激反应元件 (ISRE)。该 ISRE 通过与称为 IFN 调节因子 (IRF) 的转录因子家族的结合赋予对 IFN 信号的响应性。一些 IRF 可以单独与 DNA 结合，例如 IRF-1（引发转录激活）或 IRF-2（导致转录抑制）。此外，这些因子与 IRF-8/IFN 共有序列结合蛋白 (ICSBP)（一种免疫细胞限制的 IRF）相关，并且组装的异质复合物导致 ISRE 元件的协同抑制。 ISG15 是一个 ISG 原型，包含一个特征良好的 ISRE。在这里，我们发现 PU.1 是骨髓/淋巴细胞分化所必需的 ETS 成员，它与免疫限制性 IRF、IRF-8\ICSBP 和 IRF-4 形成异质复合物，从而导致 ISG15 的转录激活。这些数据允许对被称为 ETS/IRF 反应元件 (EIRE) 的 ISRE 子集进行表征，这些元件在免疫细胞中受到差异性调节。 EIRE 的独特之处在于它们能够招募不同的因子来组装增强体。在非免疫细胞中，因子将主要包括IRF成员，而细胞类型限制因子，例如PU.1、IRF-8\ICSBP和IRF-4，将在免疫细胞中招募。 IRF 异源复合物的形成导致转录抑制，相反，PU.1/IRFs 异源复合物的形成导致转录激活。 IRF-8\ICSBP 是 IFN-gamma 诱导因子这一事实解释了为什么一些 EIRE 也由 II 型 IFN 诱导。我们的结果为免疫细胞中含有 EIRE 的 ISG 的独特调节奠定了分子基础。
Type I IFNs cause the induction of a subset of genes termed IFN-stimulated genes (ISGs), which harbor a specific DNA element, IFN-stimulated response element (ISRE). This ISRE confers the responsiveness to the IFN signal through the binding of a family of transcription factors designated IFN regulatory factors (IRFs). Some IRFs can bind to the DNA alone, such as IRF-1, which elicits transcriptional activation, or IRF-2, which leads to transcriptional repression. In addition, these factors associate with IRF-8/IFN consensus sequence binding protein (ICSBP), an immune cell-restricted IRF, and the assembled heterocomplexes lead to synergistic repression of ISRE elements. ISG15 is a prototype ISG that contains a well-characterized ISRE. Here we show that PU.1, an ETS member essential for myeloid/lymphoid cell differentiation, forms heterocomplexes with the immune-restricted IRFs, IRF-8\ICSBP and IRF-4, which lead to transcriptional activation of ISG15. These data allowed the characterization of a subset of ISREs designated ETS/IRF response element (EIRE), which are differentially regulated in immune cells. EIREs are unique in their ability to recruit different factors to an assembled enhanceosomes. In nonimmune cells the factors will mainly include IRF members, while cell type-restricted factors, such as PU.1, IRF-8\ICSBP, and IRF-4, will be recruited in immune cells. IRF heterocomplex formation leads to transcriptional repression, and conversely, PU.1/IRFs heterocomplex formation leads to transcriptional activation. The fact that IRF-8\ICSBP is an IFN-gamma-induced factor explains why some of the EIREs are also induced by type II IFN. Our results lay the molecular basis for the unique regulation of ISGs, harboring EIRE, in immune cells.