Centrosome amplification fine tunes tubulin acetylation to differentially control intracellular organization

Abstract

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. image Cellular adaptation and response to physiological cues require the relocation of individual organelles. Here, centrosome amplification, a common feature of many cancers, is shown to promote cell migration through confined spaces due to an altered intracellular organization, which is partly regulated by tubulin acetylation. Centrosome amplification causes kinesin‐1‐dependent repositioning of various intracellular components towards the cell periphery. Increased tubulin acetylation downstream of centrosome amplification promotes the displacement of mitochondria, centrosomes, and vimentin. Increased tubulin acetylation facilitates migration through confined spaces. The positioning of centrosomes is determined by the polarized distribution of acetylated microtubules, rather than by the level of tubulin acetylation alone.