Foxp3 has been shown to be both necessary and sufficient for the development and function of naturally arising CD4+ CD25+ regulatory T cells in mice. Mutation of Foxp3 in Scurfy mice and FOXP3 in humans with IPEX results in fatal, early onset autoimmune disease and demonstrates the critical role of FOXP3 in maintaining immune homeostasis. The FOXP3 protein encodes several functional domains, including a C2H2 zinc finger, a leucine zipper, and a winged-helix/forkhead (FKH) domain. We have shown previously that FOXP3 functions as a transcriptional repressor and inhibits activation-induced IL-2 gene transcription. To characterize the role of each predicted functional domain on the in vivo activity of FOXP3, we have evaluated the location of point mutations identified in a large cohort of patients with the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) and found them to cluster primarily within the FKH domain and the leucine zipper, but also present within the poorly defined N-terminal portion of the protein. The molecular functions of each of the IPEX-targeted domains were investigated. We show that FOXP3 is constitutively localized to the nucleus and this localization requires sequences at both the amino and C-terminal ends of its FKH domain. Moreover, FOXP3 was found to homodimerize through its leucine zipper. We also identify a novel functional domain within the N-terminal half of FOXP3, which is required for FOXP3-mediated repression of transcription from both a constitutively active and a NF-AT-inducible promoter. Furthermore, we demonstrate that IPEX mutations in these domains correlate with deficiencies in FOXP3 repressor function, corroborating their in vivo relevance.

译文

已经证明:Foxp3对于小鼠中天然产生的CD4 CD25调节性T细胞的发育和功能既必要又充分。用IPEX突变的Scurfy小鼠中的Foxp3和人类中的FOXP3突变会导致致命的早期发作的自身免疫性疾病,并证明FOXP3在维持免疫稳态方面的关键作用。 FOXP3蛋白编码几个功能域,包括C2H2锌指,亮氨酸拉链和带翼螺旋/叉头(FKH)域。先前我们已经证明FOXP3充当转录阻遏物,并抑制激活诱导的IL-2基因转录。为了表征每个预测功能结构域对FOXP3体内活性的作用,我们评估了在一大批患有免疫功能异常,多内分泌病,肠病,X连锁综合征(IPEX)的患者中鉴定出的点突变的位置,并发现它们主要聚集在FKH结构域和亮氨酸拉链中,但也存在于蛋白质的N末端定义不明确的区域。研究了每个IPEX靶向域的分子功能。我们显示FOXP3组成性地定位于原子核,并且此定位需要在其FKH域的氨基和C末端都具有序列。此外,发现FOXP3通过其亮氨酸拉链同源二聚体。我们还确定了FOXP3 N末端一半内的新型功能域,这是FOXP3介导的从组成型活性启动子和NF-AT诱导型启动子转录抑制所必需的。此外,我们证明这些域中的IPEX突变与FOXP3阻遏物功能的缺陷相关,从而证实了它们的体内相关性。

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