Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
Institut Curie, Paris Sciences and Lettres Research University, Centre National de la Recherche Scientifique, UMR144, Paris, France.
EMBO J. 2023 Aug 15;42(16):e112812. doi: 10.15252/embj.2022112812. Epub 2023 Jul 5.
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.
细胞内细胞器的组织在真核细胞中是保守的，主要通过沿微管细胞骨架的马达蛋白的主动运输来实现。微管的翻译后修饰（PTMs）可以促进微管的多样性，并对马达蛋白介导的运输进行差异调节。在这里，我们表明，中心体扩增，常见于癌症，并被证明促进非整倍体和侵袭，诱导细胞器位置向细胞外周的全局变化，并通过限制空间促进核迁移。这种重排需要驱动蛋白-1（kinesin-1），类似于动力蛋白的丧失。扩增中心体的细胞显示乙酰化微管的水平增加，这种翻译后修饰可以增强驱动蛋白-1 介导的运输。通过耗尽 α-微管乙酰转移酶 1（αTAT1）来阻止微管乙酰化，挽救了中心体、线粒体和波形蛋白的位移，但不能挽救高尔基体或内体。对总微管和乙酰化微管分布的分析表明，修饰微管的极化分布，而不仅仅是水平，在特定细胞器（如中心体）的定位中起着重要作用。我们提出，增加的微管乙酰化差异影响驱动蛋白-1 介导的细胞器位移，以调节细胞内组织。
