Wnt/β-catenin-dependent acetylation of Pygo2 by CBP/p300 histone acetyltransferase family members
Wnt/β-catenin-dependent acetylation of Pygo2 by CBP/p300 histone acetyltransferase family members
复制标题
DOI：
10.1042/bcj20160590
复制
发表时间：
2016-11-15
影响因子：
4.1
通讯作者：
Kao, Kenneth R.
中科院分区：
文献类型：
--
作者：
Andrews, Phillip G. P.;Kao, Kenneth R.
Pygopus 2（Pygo 2）是一种染色质效应子，在与发育和干细胞生长相关的经典Wnt信号传导中发挥重要作用。其功能是通过在β-连环蛋白介导的转录的活性位点募集组蛋白乙酰转移酶（HAT）来促进组蛋白乙酰化。在本研究中，我们报告说，Pygo 2本身是短暂的乙酰化时，结合到激活的TCF/β-catenin转录复合物，这与β-catenin结合和Axin 2基因激活。HAT CBP/p300，而不是GCN 5/PCAF，靶向Pygo 2的N-末端同源结构域的特异性赖氨酸残基进行乙酰化。功能分析显示CBP和p300的存在增加了Pygo 2与GCN 5的结合，而与Pygo 2乙酰化状态无关。最后，虽然Pygo 2的乙酰化对活性β-连环蛋白复合物的形成几乎没有影响，但p300介导的Pygo 2乙酰化通过靶向Pygo 2核定位序列中的特异性赖氨酸残基导致Pygo 2从细胞核置换到细胞质。总之，这些发现与这样一种模型一致，即活性TCF/β-连环蛋白复合物中CBP/p300家族成员对Pygo 2的乙酰化与组蛋白乙酰化同时发生，并且可能是靶基因激活后Pygo 2从复合物中回收所需的。
Pygopus 2 (Pygo2) is a chromatin effector that plays an essential role in canonical Wnt signaling associated with development and stem cell growth. Its function is to facilitate histone acetylation by recruitment of histone acetyltransferases (HATs) at active sites of beta-catenin-mediated transcription. In the present study, we report that Pygo2 itself is transiently acetylated when bound to the activated TCF/beta-catenin transcription complex, which correlated with beta-catenin binding and Axin2 gene activation. The HAT CBP/p300, but not GCN5/PCAF, targeted specific lysine residues of the N-terminal homology domain of Pygo2 for acetylation. Functional analyses revealed that the presence of CBP and p300 increased the association of Pygo2 with GCN5, independent of Pygo2 acetylation status. Finally, while acetylation of Pygo2 had little effect on active beta-catenin complex formation, p300-mediated Pygo2 acetylation resulted in the displacement of Pygo2 from the nucleus to the cytoplasm by targeting specific lysine residues in the Pygo2 nuclear localization sequence. Taken together, these findings are consistent with a model in which acetylation of Pygo2 by CBP/p300 family members in the active TCF/beta-catenin complex occurs coincident with histone acetylation and may be required for the recycling of Pygo2 away from the complex subsequent to target gene activation.