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

Foxp3已被证明对于小鼠中自然产生的CD4 CD25调节性T细胞的发育和功能既必要又充分。在患有pex的Scurfy小鼠中Foxp3和人类中FOXP3的突变会导致致命的,早发性自身免疫性疾病,并证明了FOXP3在维持免疫稳态中的关键作用。FOXP3蛋白编码几个功能结构域,包括C2H2锌指,亮氨酸拉链和有翼螺旋/叉头 (FKH) 结构域。我们先前已经证明FOXP3作为转录阻遏物起作用并抑制激活诱导的IL-2基因转录。为了表征每个预测的功能域对FOXP3体内活性的作用,我们评估了在免疫失调,多内分泌病,肠病,X连锁综合征 (IPEX),发现它们主要聚集在FKH结构域和亮氨酸拉链内,但也存在于蛋白质定义不明确的N端部分。研究了每个pex靶向域的分子功能。我们证明FOXP3组成性地定位于细胞核,并且这种定位需要在其FKH结构域的氨基和C末端都具有序列。此外,发现FOXP3通过其亮氨酸拉链同向二聚。我们还在FOXP3的N末端一半内鉴定了一个新的功能结构域,这是FOXP3-mediated抑制组成型活性和NF-AT诱导启动子转录所必需的。此外,我们证明了这些域中的IPEX突变与FOXP3阻遏物功能的缺陷相关,从而证实了它们在体内的相关性。

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