Li Bin, Samanta Arabinda, Song Xiaomin, Iacono Kathryn T, Bembas Kathryn, Tao Ran, Basu Samik, Riley James L, Hancock Wayne W, Shen Yuan, Saouaf Sandra J, Greene Mark I
Department of Pathology and Laboratory Medicine, University of Pennsylvania, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, USA.
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4571-6. doi: 10.1073/pnas.0700298104. Epub 2007 Mar 7.
The forkhead family protein FOXP3 acts as a repressor of transcription and is both an essential and sufficient regulator of the development and function of regulatory T cells. The molecular mechanism by which FOXP3-mediated transcriptional repression occurs remains unclear. Here, we report that transcriptional repression by FOXP3 involves a histone acetyltransferase-deacetylase complex that includes histone acetyltransferase TIP60 (Tat-interactive protein, 60 kDa) and class II histone deacetylases HDAC7 and HDAC9. The N-terminal 106-190 aa of FOXP3 are required for TIP60-FOXP3, HDAC7-FOXP3 association, as well as for the transcriptional repression of FOXP3 via its forkhead domain. FOXP3 can be acetylated in primary human regulatory T cells, and TIP60 promotes FOXP3 acetylation in vivo. Overexpression of TIP60 but not its histone acetyltransferase-deficient mutant promotes, whereas knockdown of endogenous TIP60 relieved, FOXP3-mediated transcriptional repression. A minimum FOXP3 ensemble containing native TIP60 and HDAC7 is necessary for IL-2 production regulation in T cells. Moreover, FOXP3 association with HDAC9 is antagonized by T cell stimulation and can be restored by the protein deacetylation inhibitor trichostatin A, indicating a complex dynamic aspect of T suppressor cell regulation. These findings identify a previously uncharacterized complex-based mechanism by which FOXP3 actively mediates transcriptional repression.
叉头框蛋白家族成员FOXP3作为转录抑制因子，是调节性T细胞发育和功能的必需且充分的调节因子。FOXP3介导的转录抑制发生的分子机制仍不清楚。在此，我们报道FOXP3介导的转录抑制涉及一种组蛋白乙酰转移酶-去乙酰化酶复合物，该复合物包括组蛋白乙酰转移酶TIP60（Tat相互作用蛋白，60 kDa）以及II类组蛋白去乙酰化酶HDAC7和HDAC9。FOXP3的N端106 - 190个氨基酸对于TIP60 - FOXP3、HDAC7 - FOXP3的结合以及通过其叉头结构域进行的FOXP3转录抑制是必需的。FOXP3在原代人调节性T细胞中可被乙酰化，并且TIP60在体内促进FOXP3的乙酰化。TIP60的过表达而非其组蛋白乙酰转移酶缺陷型突变体促进了FOXP3介导的转录抑制，而内源性TIP60的敲低则减轻了这种抑制。包含天然TIP60和HDAC7的最小FOXP3聚合体对于T细胞中IL - 2的产生调节是必需的。此外，T细胞刺激可拮抗FOXP3与HDAC9的结合，并且蛋白去乙酰化抑制剂曲古抑菌素A可恢复这种结合，这表明调节性T细胞调节存在复杂的动态变化。这些发现确定了一种以前未被描述的基于复合物的机制，通过该机制FOXP3可积极介导转录抑制。
