EB1 acetylation by P300/CBP-associated factor (PCAF) ensures accurate kinetochore-microtubule interactions in mitosis
EB1 acetylation by P300/CBP-associated factor (PCAF) ensures accurate kinetochore-microtubule interactions in mitosis
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DOI：
10.1073/pnas.1202639109
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发表时间：
2012-10-09
影响因子：
11.1
通讯作者：
Yao, Xuebiao
中科院分区：
文献类型：
--
作者：
Xia, Peng;Wang, Zhikai;Yao, Xuebiao
在真核生物中，微管对于细胞的可塑性和动力学是必不可少的。在这里，我们表明，P300/CBP相关因子（PCAF），一个kinetochorse相关的乙酰转移酶，作为微管稳定性的负调制器通过乙酰化EB 1，一种蛋白质，控制微管的正端。PCAF乙酰化K220上的EB 1并破坏二聚化EB 1 C末端上的疏水腔的稳定性，该疏水腔先前被报道与含有SxIP基序的正末端跟踪蛋白（TIP）相互作用。如用EB 1乙酰基-K220特异性抗体所确定的，K220乙酰化在有丝分裂中显著增加，并定位于纺锤体微管加末端。令人惊讶的是，EB 1的持续乙酰化延迟了中期对齐，导致检查点沉默受损。因此，Mad 2的抑制覆盖了由持续的EB 1乙酰化诱导的有丝分裂阻滞。因此，我们的研究结果确定EB 1的动态乙酰化作为一种分子机制，以协调准确的有丝分裂中的kinetochore-microtubule相互作用。这些结果建立了一个以前没有特点的监管机制，管理本地化的微管加端跟踪蛋白，从而可塑性和动态的细胞。
In eukaryotes, microtubules are essential for cellular plasticity and dynamics. Here we show that P300/CBP-associated factor (PCAF), a kinetochore-associated acetyltransferase, acts as a negative modulator of microtubule stability through acetylation of EB1, a protein that controls the plus ends of microtubules. PCAF acetylates EB1 on K220 and disrupts the stability of a hydrophobic cavity on the dimerized EB1 C terminus, which was previously reported to interact with plus-end tracking proteins (TIPs) containing the SxIP motif. As determined with an EB1 acetyl-K220-specific antibody, K220 acetylation is dramatically increased in mitosis and localized to the spindle microtubule plus ends. Surprisingly, persistent acetylation of EB1 delays metaphase alignment, resulting in impaired checkpoint silencing. Consequently, suppression of Mad2 overrides mitotic arrest induced by persistent EB1 acetylation. Thus, our findings identify dynamic acetylation of EB1 as a molecular mechanism to orchestrate accurate kinetochore-microtubule interactions in mitosis. These results establish a previously uncharacterized regulatory mechanism governing localization of microtubule plus-end tracking proteins and thereby the plasticity and dynamics of cells.