Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis
Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax-mediated apoptosis
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DOI：
10.1016/s1097-2765(04)00094-2
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发表时间：
2004-03-12
期刊：
影响因子：
16
通讯作者：
Sinclair, DA
中科院分区：
文献类型：
--
作者：
Cohen, HY;Lavu, S;Sinclair, DA
细胞凋亡是一种关键的肿瘤抑制机制，它可以通过激活促凋亡因子Bax来启动。Ku70 DNA末端连接蛋白最近被证明通过隔离线粒体中的Bax来抑制细胞凋亡。Bax受调控的机制尚不清楚。在这里，我们鉴定了Ku70中的8种赖氨酸，它们是体内乙酰化的靶点。其中K539、K542、K544、K533和K556五个位于Ku70的c端连接子结构域，与Bax相互作用结构域相邻。我们发现CBP和PCAF在体外有效乙酰化K542，并在体内与Ku70结合。模拟K539或K542的乙酰化或用去乙酰化酶抑制剂处理细胞可消除Ku70抑制bax介导的细胞凋亡的能力。我们证明，Ku70乙酰化的增加破坏了Ku70- bax的相互作用，并与CBP的细胞质积累相一致。这些结果阐明了乙酰转移酶作为肿瘤抑制因子的作用。
Apoptosis is a key tumor suppression mechanism that can be initiated by activation of the proapoptotic factor Bax. The Ku70 DNA end-joining protein has recently been shown to suppress apoptosis by sequestering Bax from mitochondria. The mechanism by which Bax is regulated remains unknown. Here, we identify eight lysines in Ku70 that are targets for acetylation in vivo. Five of these, K539, K542, K544, K533, and K556, lie in the C-terminal linker domain of Ku70 adjacent to the Bax interaction domain. We show that CBP and PCAF efficiently acetylate K542 in vitro and associate with Ku70 in vivo. Mimicking acetylation of K539 or K542 or treating cells with deacetylase inhibitors abolishes the ability of Ku70 to suppress Bax-mediated apoptosis. We demonstrate that increased acetylation of Ku70 disrupts the Ku70-Bax interaction and coincides with cytoplasmic accumulation of CBP. These results shed light on the role of acetyltransferases as tumor suppressors.