Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
PLoS One. 2009 Nov 18;4(11):e7890. doi: 10.1371/journal.pone.0007890.
Foxp3, a 47-kDa transcription factor, is necessary for the function of CD4+CD25+ regulatory T cells (Tregs), with an essential role in the control of self-reactive T cells and in preventing autoimmunity. Activation of Tregs by TCR engagement results in upregulation of Foxp3 expression, followed by its rapid nuclear transport and binding to chromatin. Here, we identify three distinct Foxp3 domains that contribute to nuclear transport. The first domain (Domain 1) comprises the C-terminal 12 amino acids. The second domain (Domain 2) is located immediately N-terminal to the forkhead domain (FHD), recently reported to be a binding site for the runt-related transcription factor 1/acute myeloid leukemia 1 (Runx1/AML1). The third domain (Domain 3) is located within the N-terminal first 51 amino acids. Unlike the known nuclear localization signals (NLSs), none of these three regions are rich in basic residues and do not bear any similarity to known monopartite or bipartite NLSs that have one or more clusters of basic amino acids. The basic arginine-lysine-lysine-arginine (RKKR) sequence, located 12-aa from the C-terminal end of Foxp3 was previously reported to be a nuclear localization signal (NLS) for several proteins, including for a GFP-Foxp3 hybrid. Evidence is provided here that in the full-length native Foxp3 RKKR does not function as an NLS. The data reported in this study indicates that Foxp3 achieves nuclear transport by binding to other nuclear factors and co-transporting with them to the nucleus.
Foxp3 是一种 47kDa 的转录因子，对于 CD4+CD25+调节性 T 细胞（Tregs）的功能是必需的，在控制自身反应性 T 细胞和防止自身免疫方面起着重要作用。TCR 结合激活 Tregs 会导致 Foxp3 表达上调，随后其快速核转运并与染色质结合。在这里，我们确定了三个不同的 Foxp3 结构域有助于核转运。第一个结构域（结构域 1）包含 C 端的 12 个氨基酸。第二个结构域（结构域 2）位于 forkhead 结构域（FHD）的 N 端，最近报道该结构域是 runt 相关转录因子 1/急性髓系白血病 1（Runx1/AML1）的结合位点。第三个结构域（结构域 3）位于 N 端的前 51 个氨基酸内。与已知的核定位信号（NLS）不同，这三个区域都没有富含碱性残基，也没有与已知的单部分或双部分 NLS 相似，这些 NLS 具有一个或多个碱性氨基酸簇。位于 Foxp3 C 端末端 12 个氨基酸处的碱性精氨酸-赖氨酸-赖氨酸-精氨酸（RKKR）序列先前被报道为包括 GFP-Foxp3 杂合体在内的几种蛋白质的核定位信号（NLS）。本研究提供的证据表明，在全长天然 Foxp3 中，RKKR 不作为 NLS 发挥作用。本研究报告的数据表明，Foxp3 通过与其他核因子结合并与它们一起转运到核内来实现核转运。
