Gamma interferon triggers interaction between ICSBP (IRF-8) and TEL, recruiting the histone deacetylase HDAC3 to the interferon-responsive element
Gamma interferon triggers interaction between ICSBP (IRF-8) and TEL, recruiting the histone deacetylase HDAC3 to the interferon-responsive element
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DOI：
10.1128/mcb.22.21.7439-7448.2002
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发表时间：
2002-11-01
影响因子：
5.3
通讯作者：
Ozato, K
中科院分区：
文献类型：
--
作者：
Kuwata, T;Gongora, C;Ozato, K
ICSBP(IRF-8)是IRF家族的一种转录因子，仅在免疫系统中表达。它在巨噬细胞中由干扰素(干扰素-γ)诱导，并有助于巨噬细胞的功能。ICSBP通过与ETS家族蛋白PU.1相互作用，与IRF/ETS复合元件结合并刺激转录。ICSBP与另一种DNA元件--干扰素刺激反应元件(ISRE)结合，这是IRF家族的共同靶标。关于ICSBP和其他IRF蛋白如何在WN-Y激活的巨噬细胞中调节ISRE依赖的转录的知识有限。通过对巨噬细胞中ISRE结合蛋白的质谱分析，我们确定了ETS的另一个成员TEL是以依赖于干扰素的方式招募到该元件的一个因子。重组蛋白的体外分析表明，这种募集是由于ICSBP和TEL之间的直接相互作用，这种作用在ISRE的存在下得到了加强。值得注意的是，与TEL的相互作用反过来导致组蛋白去乙酰酶HDAC3被招募到ISRE，导致通过ISRE对干扰素-γ介导的报告活性的抑制增加。这种抑制可能提供了一种负反馈机制，在干扰素-γ最初转录激活后进行操作。ICSBP通过与两种不同的ETS家族蛋白结合，以免疫系统特异性的方式在干扰素依赖的基因调控中发挥双重功能。
ICSBP (IRF-8) is a transcription factor of the IRF family expressed only in the immune system. It is induced in macrophages by gamma interferon (IFN-gamma) and contributes to macrophage functions. By interacting with Ets family protein PU.1, ICSBP binds to the IRF/Ets composite element and stimulates transcription. ICSBP binds to another DNA element, the IFN-stimulated response element (ISRE), a common target of the IRF family. Limited knowledge as to how ICSBP and other IRF proteins regulate ISRE-dependent transcription in WN-y-activated macrophages is available. By mass-spectrometric analysis of ISRE-bound proteins in macrophages, we identified TEL, another Ets member, as a factor recruited to the element in an IFN-y-dependent manner. In vitro analysis with recombinant proteins indicated that this recruitment is due to a direct interaction between ICSBP and TEL, which is enhanced by the presence of ISRE. Significantly, the interaction with TEL in turn resulted in the recruitment of the histone deacetytase HDAC3 to the ISRE, causing increased repression of IFN-y-mediated reporter activity through the ISRE. This repression may provide a negative-feedback mechanism operating after the initial transcriptional activation by IFN-y. By associating with two different Ets family proteins, ICSBP exerts a dual function in IFN-y-dependent gene regulation in an immune system-specific manner.