FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression
FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression
复制标题
DOI：
10.1073/pnas.0700298104
复制
发表时间：
2007-03-13
影响因子：
11.1
通讯作者：
Greene, Mark I.
中科院分区：
文献类型：
--
作者：
Li, Bin;Samanta, Arabinda;Greene, Mark I.
叉头家族蛋白FOXP 3作为转录的阻遏物起作用，并且是调节性T细胞的发育和功能的必要且充分的调节剂。FOXP 3介导的转录抑制发生的分子机制仍不清楚。在这里，我们报告转录抑制FOXP 3涉及组蛋白乙酰转移酶-脱乙酰酶复合物，包括组蛋白乙酰转移酶TIP 60（Tat相互作用蛋白，60 kDa）和II类组蛋白脱乙酰酶HDAC 7和HDAC 9。FOXP 3的N-末端106-190 aa是TIP 60-FOXP 3、HDAC 7-FOXP 3缔合以及FOXP 3通过其叉头结构域的转录抑制所必需的。FOXP 3可以在原代人调节性T细胞中被乙酰化，并且TIP 60在体内促进FOXP 3乙酰化。过表达的TIP 60，而不是其组蛋白乙酰转移酶缺陷的突变体促进，而内源性TIP 60敲低解除，FOXP 3介导的转录抑制。含有天然TIP 60和HDAC 7的最小FOXP 3系综对于T细胞中的IL-2产生调节是必需的。此外，FOXP 3与HDAC 9的关联被T细胞刺激拮抗，并且可以被蛋白质脱乙酰化抑制剂阿司他丁A恢复，表明T抑制细胞调控的复杂动态方面。这些发现确定了一个以前未表征的复合物为基础的机制，FOXP 3积极介导转录抑制。
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.