Interferon Regulatory Factor 2 Binding Protein 2 Is a New NFAT1 Partner and Represses Its Transcriptional Activity
Interferon Regulatory Factor 2 Binding Protein 2 Is a New NFAT1 Partner and Represses Its Transcriptional Activity
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DOI：
10.1128/mcb.00974-10
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发表时间：
2011-07-01
影响因子：
5.3
通讯作者：
Viola, Joao P. B.
中科院分区：
文献类型：
--
作者：
Carneiro, Flavia R. G.;Ramalho-Oliveira, Renata;Viola, Joao P. B.
活化T细胞核因子（NFAT）家族转录因子在多种细胞类型中表达，并调节参与细胞周期、分化和凋亡的基因。NFAT蛋白共享两个保守区域，即调控结构域和DNA结合结构域。N端和c端是反激活位点，序列相似性较低，而它们的分子功能尚不清楚。在这里，我们发现了一个转录抑制因子，干扰素调节因子2结合蛋白2 (IRF-2BP2)，它在NFAT家族成员中特异性地与NFAT1的c端结构域相互作用。IRF-2BP2通过抑制增强子激活和基础转录被描述为一种辅助抑制因子。基因报告基因实验表明，IRF-2BP2抑制nfat1依赖性启动子的转激活。IRF-2BP2在CD4 T细胞中的异位表达导致白细胞介素-2 （IL-2）和IL-4的产生减少，支持IRF-2BP2对NFAT靶基因的抑制功能。此外，NFAT1和IRF-2BP2在活化细胞的细胞核中共定位，IRF-2BP2中一个新发现的核定位信号的突变使其成为细胞质，从而消除了其对NFAT1活性的抑制作用。总的来说，我们的数据表明，IRF-2BP2是NFAT1转录因子的负调节因子，并表明NFAT1抑制发生在转录水平。
The nuclear factor of activated T cells (NFAT) family of transcription factors is expressed in a wide range of cell types and regulates genes involved in cell cycle, differentiation, and apoptosis. NFAT proteins share two well-conserved regions, the regulatory domain and the DNA binding domain. The N- and C-terminal ends are transactivation sites and show less sequence similarity, whereas their molecular functions remain poorly understood. Here, we identified a transcriptional repressor, interferon regulatory factor 2 binding protein 2 (IRF-2BP2), which specifically interacts with the C-terminal domain of NFAT1 among the NFAT family members. IRF-2BP2 was described as a corepressor by inhibiting both enhancer-activated and basal transcription. Gene reporter assays demonstrated that IRF-2BP2 represses the NFAT1-dependent transactivation of NFAT-responsive promoters. The ectopic expression of IRF-2BP2 in CD4 T cells resulted in decreased interleukin-2 (IL-2) and IL-4 production, supporting a repressive function of IRF-2BP2 for NFAT target genes. Furthermore, NFAT1 and IRF-2BP2 colocalized in the nucleus in activated cells, and the mutation of a newly identified nuclear localization signal in the IRF-2BP2 rendered it cytoplasmic, abolishing its repressive effect on NFAT1 activity. Collectively, our data demonstrate that IRF-2BP2 is a negative regulator of the NFAT1 transcription factor and suggest that NFAT1 repression occurs at the transcriptional level.