Centrosome amplification fine-tunes tubulin acetylation to differentially control intracellular organization
Centrosome amplification fine-tunes tubulin acetylation to differentially control intracellular organization
复制标题
中心体扩增微调微管蛋白乙酰化以差异控制细胞内组织
DOI：
10.1101/2022.10.17.512471
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Monteiro P
中科院分区：
文献类型：
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作者：
Monteiro P
细胞内细胞器组织在真核细胞中是保守的，并且主要通过马达蛋白沿着微管细胞骨架沿着的主动运输来实现。微管翻译后修饰（PTM）可以促进微管多样性并差异调节运动介导的转运。在这里，我们表明，中心体扩增，通常在癌症中观察到，并显示促进非整倍体和入侵，诱导细胞器定位向细胞周边的全球变化，并促进通过有限的空间核迁移。这种重组需要驱动蛋白-1，类似于动力蛋白的丢失。具有扩增的中心体的细胞显示乙酰化微管蛋白水平增加，这是一种可以增强驱动蛋白1介导的转运的PTM。消耗α-微管蛋白乙酰转移酶1（α TAT 1）以阻断微管蛋白乙酰化可挽救中心体、线粒体和波形蛋白的移位，但不能挽救高尔基体或内体的移位。总的和乙酰化微管的分布分析表明，修饰微管的极化分布，而不是单独的水平，在特定的细胞器，如中心体的定位中起着重要的作用。我们提出，增加微管蛋白乙酰化差异影响驱动蛋白1介导的细胞器位移，以调节细胞内的组织。
Intracellular organelle organization is conserved in eukaryotic cells and is primarily achieved through active transport by motor proteins along the microtubule cytoskeleton. Microtubule post‐translational modifications (PTMs) can contribute to microtubule diversity and differentially regulate motor‐mediated transport. Here, we show that centrosome amplification, commonly observed in cancer and shown to promote aneuploidy and invasion, induces a global change in organelle positioning towards the cell periphery and facilitates nuclear migration through confined spaces. This reorganization requires kinesin‐1 and is analogous to the loss of dynein. Cells with amplified centrosomes display increased levels of acetylated tubulin, a PTM that could enhance kinesin‐1‐mediated transport. Depletion of α‐tubulin acetyltransferase 1 (αTAT1) to block tubulin acetylation rescues the displacement of centrosomes, mitochondria, and vimentin but not Golgi or endosomes. Analyses of the distribution of total and acetylated microtubules indicate that the polarized distribution of modified microtubules, rather than levels alone, plays an important role in the positioning of specific organelles, such as the centrosome. We propose that increased tubulin acetylation differentially impacts kinesin‐1‐mediated organelle displacement to regulate intracellular organization.