Meraro D, Hashmueli S, Koren B, Azriel A, Oumard A, Kirchhoff S, Hauser H, Nagulapalli S, Atchison M L, Levi B Z
Department of Food Engineering and Biotechnology, Technion, Haifa, Israel.
J Immunol. 1999 Dec 15;163(12):6468-78.
IFN regulatory factors (IRFs) constitute a family of transcription factors that are involved in IFN signaling and the development and differentiation of the immune system. Targeted gene disruption studies in mice assigned their primary role to the immune system. Two lymphoid-specific IRF members, IFN consensus sequence binding protein (ICSBP) and IRF-4, bind target DNA with greater efficiency following interaction with two transcription factors, PU.1 and E47, leading to transcriptional synergy. PU.1 and E47 are essential for proper differentiation and maturation of lymphoid cells. In addition, ICSBP interacts with two IRF members, IRF-1 and IRF-2, which also have central roles in the regulation of cell-mediated immunity. Previously, we identified a region in ICSBP, termed the IRF association domain (IAD), that is conserved in all IRFs (excluding IRF-1 and IRF-2) and is essential for its interactions with other IRF proteins. Here we show that the IAD is an independent module used by ICSBP and IRF-4 for protein-protein interactions. In addition, an IAD of IRF-2 (IAD2), necessary for interaction with ICSBP, was identified and found to be conserved in IRF-1. The IAD2 shares similar characteristics with the PEST domain that is essential for the interaction of PU.1 with IRF-4. We also show that the ICSBP DNA binding domain is indispensable for the formation of DNA binding heterocomplexes and transcriptional activity. Therefore, our results shed light on the molecular mechanisms that affect IRF activities in the immune system via discrete functional domains.
干扰素调节因子（IRFs）构成了一类转录因子家族，它们参与干扰素信号传导以及免疫系统的发育和分化。在小鼠中进行的靶向基因敲除研究确定了它们在免疫系统中的主要作用。两个淋巴样特异性IRF成员，即干扰素共有序列结合蛋白（ICSBP）和IRF-4，在与两个转录因子PU.1和E47相互作用后，能更高效地结合靶DNA，从而导致转录协同作用。PU.1和E47对于淋巴样细胞的正常分化和成熟至关重要。此外，ICSBP与另外两个IRF成员IRF-1和IRF-2相互作用，这两个成员在细胞介导的免疫调节中也起着核心作用。此前，我们在ICSBP中鉴定出一个区域，称为IRF关联域（IAD），该区域在所有IRF（不包括IRF-1和IRF-2）中都保守，并且对于其与其他IRF蛋白的相互作用至关重要。在此我们表明，IAD是ICSBP和IRF-4用于蛋白质-蛋白质相互作用的一个独立模块。此外，还鉴定出了IRF-2与ICSBP相互作用所必需的IAD（IAD2），并发现其在IRF-1中保守。IAD2与PU.1和IRF-4相互作用所必需的PEST结构域具有相似的特征。我们还表明，ICSBP的DNA结合结构域对于DNA结合异源复合物的形成和转录活性是不可或缺的。因此，我们的结果揭示了通过离散功能域影响免疫系统中IRF活性的分子机制。
