Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3663-8. doi: 10.1073/pnas.0914700107. Epub 2010 Feb 4.
Nuclear factor of activated T cell (NFAT) transcription factors are key regulators of gene transcription within immune cells. The NFAT-interacting protein, (NIP45), augments NFAT-driven IL-4 expression by a mechanism that relies on arginine methylation. To establish the function of NIP45 in vivo, we generated mice with a targeted deletion of the gene encoding this cofactor. NIP45-deficient T helper cells displayed profound defects in the expression of NFAT-regulated cytokine genes, including IL-4. Whereas NIP45 deficiency does not interfere with T helper cell NFAT activation or lineage-specific transcription-factor expression, NIP45 acts as an enhancer for the assembly of protein arginine methyltransferase 1 and the protein arginine methyltransferase 1-linked histone 4 arginine 3 methylation with the IL-4 promoter. Our study reveals an essential role for NIP45 in promoting robust cytokine expression in vivo, which is required for the efficient handling of parasites. We propose that NIP45 acts as a molecular rheostat serving to amplify the type-2 immune response.
活化 T 细胞核因子（NFAT）转录因子是免疫细胞内基因转录的关键调节因子。NFAT 相互作用蛋白（NIP45）通过依赖精氨酸甲基化的机制增强 NFAT 驱动的 IL-4 表达。为了在体内建立 NIP45 的功能，我们生成了基因编码这种共因子的靶向缺失小鼠。缺乏 NIP45 的辅助性 T 细胞显示出 NFAT 调节的细胞因子基因表达的深刻缺陷，包括 IL-4。尽管 NIP45 缺失不干扰辅助性 T 细胞 NFAT 激活或谱系特异性转录因子表达，但 NIP45 作为蛋白质精氨酸甲基转移酶 1 和蛋白质精氨酸甲基转移酶 1 相关的组蛋白 4 精氨酸 3 甲基化与 IL-4 启动子组装的增强子。我们的研究揭示了 NIP45 在促进体内强大细胞因子表达中的重要作用，这对于有效处理寄生虫是必需的。我们提出 NIP45 作为一种分子变阻器，用于放大 2 型免疫反应。
