Interferon regulatory factor 4 (IRF4) is a crucial transcription factor that plays a vital role in lymphocyte development, including in the fate-determining steps in terminal differentiation. It is also implicated in the development of lymphoid tumors such as multiple myeloma and adult T-cell leukemia. IRF4 can form a homodimer and multiple heterocomplexes with other transcription factors such as purine-rich box1 and activator protein 1. Each protein complex binds to specific DNA sequences to regulate a distinct set of genes. However, the precise relationship among these complex formations remains unclear. Herein, we investigated the abilities of IRF4 proteins with functional mutations in the IRF-association domain and autoinhibitory region to form complexes using luciferase reporter assays. The assays allowed us to selectively assess the activity of each complex. Our results revealed that certain IRF-association domain mutants, previously known to have impaired heterocomplex formation, maintained or even enhanced homodimer activity. This discrepancy suggests that the mutated amino acid residues selectively influence homodimer activity. Conversely, a phosphomimetic serine mutation in the autoinhibitory region displayed strong activating effects in all complexes. Furthermore, we observed that partner proteins involved in heterocomplex formation could disrupt the activity of the homodimer, suggesting a potential competition between homocomplexes and heterocomplexes. Our findings provide new insights into the mechanistic function of IRF4.

中文翻译：

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评估干扰素调节因子 4 复合物的形成：同源复合物与突变诱导的异源复合物的差异行为

干扰素调节因子 4 (IRF4) 是一种重要的转录因子，在淋巴细胞发育中发挥着至关重要的作用，包括在终末分化的命运决定步骤中。它还与淋巴肿瘤（如多发性骨髓瘤和成人 T 细胞白血病）的发展有关。IRF4 可以与其他转录因子（例如富含嘌呤的 box1 和激活蛋白 1）形成同源二聚体和多个异源复合物。每个蛋白复合物与特定的 DNA 序列结合，以调节一组不同的基因。然而，这些复杂结构之间的确切关系仍不清楚。在此，我们使用荧光素酶报告基因测定研究了 IRF 关联结构域和自抑制区域中具有功能突变的 IRF4 蛋白形成复合物的能力。这些测定使我们能够选择性地评估每种复合物的活性。我们的结果表明，某些先前已知会损害异源复合物形成的 IRF 关联结构域突变体维持甚至增强了同二聚体活性。这种差异表明突变的氨基酸残基选择性地影响同型二聚体活性。相反，自抑制区域的磷模拟丝氨酸突变在所有复合物中都显示出强烈的激活作用。此外，我们观察到参与异源复合物形成的伙伴蛋白可能会破坏同源二聚体的活性，这表明同源复合物和异源复合物之间存在潜在的竞争。我们的研究结果为 IRF4 的机制功能提供了新的见解。